Fixed dosages of t cell modulatory polypeptides comprising HPV peptide-MHC complexes

Abstract

This disclosure provides pharmaceutical compositions comprising a fixed dose of a dimeric T cell modulatory proteins (DTMPs) comprising peptide-MHC complexes (pMHCs) that present an HPV peptide, and methods of treating an individual in need thereof by administering a fixed dose of a DTMP. The pharmaceutical compositions comprise a fixed dose of a DTMP, and the methods comprise administering a fixed dose of a DTMP to an individual regardless of the weight of the individual. Also provided are kits useful for administering a fixed dose of the DTMP.

Description

Attorney Docket No. 33194-0001 WOFIXED DOSAGES OF T CELL MODULATORY POLYPEPTIDES COMPRISING HPV PEPTIDE-MHC COMPLEXESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 692,010, filed September 6, 2024, which application is incorporated herein by reference in its entirety.INCORPORA TION-BY-REFERENCE OF MATERIAL ELECTRONICALLY SUBMITTED

[0002] A Sequence Listing is provided herewith as 35194-0001 W0_SL.xml and is 66,265 bytes in size, created on September 5, 2025. The contents of the Sequence Listing XML are incorporated by reference herein in their entirety.

[0003] Novel proteins have been disclosed for selectively modulating T cells that can bind to and kill HPV-associated cancer cells. See Published PCT applications WO2018 / 119114, WO2020 / 132136, and WO2022 / 197970 to Cue Biopharma, Inc., which disclose heterodimeric and single-chain fusion T cell modulatory proteins (TMPs) comprising peptide-MHC complexes (pMHCs) that present an HPV-derived peptide, and dimeric TMPs or “DTMPs” that are homodimers and heterodimers comprising two of such TMPs. Such proteins also have been disclosed for coadministration with CAR-T cells that comprise a chimeric antigen receptor (i.e., a “CAR”) that binds to antigens on cancer cells. See e g., published PCT applications WO2021 / 081232 and WO2023 / 212551 to Cue Biopharma, Inc. Except as otherwise noted, as used herein the term “DTMP” denotes a homodimer or heterodimer comprising two TMPs, where one or both TMPs (typically both) comprise a pMHC that present an HPV-derived peptide.

[0004] Such novel proteins include CUE-101, which is a homodimer comprised of two identical heterodimers. Each heterodimer comprises a peptide-human leukocyte antigen (HLA) complex containing a peptide from the human papilloma virus (HPV) 16 E7 protein, two reduced-affinity, variant human interleukin-2 (IL -2) polypeptides, and a variant immunoglobulin G1 (IgGl) Fc domain comprising amino acid substitutions that substantially eliminate antibody-dependent cell- mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC). CUE-101 is designed to selectively activate tumor antigen-specific T cells to eradicate HPV16-driven cancers.Attorney Docket No. 33194-0001 WOThe heterodimers are linked together by two disulfide bonds that join two cysteine residues in the IgGl Fc polypeptide of one heterodimer to two cysteine residues in the IgGl Fc polypeptide of the other heterodimer.

[0005] As discussed in more detail below, CUE-101 has been involved in an ongoing clinical study, CUE-101-01 (NCT03978689). This study is a first-in-human (FIH) Phase I, open label, 4- part dose escalation / expansion study for evaluation of various properties of CUE-101 in patients with advanced head and neck squamous cell carcinoma (HNSCC).

[0006] One important purpose of a Phase I clinical study such as the CUE-101-01 study is to learn about the pharmacokinetics (PK) of the study drug. Several factors can influence the PK of a drug in a human patient, which factors can be broadly categorized into patient-related and drug-related factors. Both are discussed below.

[0007] Patient-Related Factors can include:• Age: patients may have altered drug metabolism and excretion rate depending on their age;• Genetics: genetic variations can affect enzyme activity and drug transporters, influencing how a drug is metabolized and eliminated;• Renal and Hepatic Function: impaired kidney or liver function can significantly affect drug clearance from the body;• Body Weight and Composition: obesity or low body weight can alter the volume of distribution and the concentration of the drug in the body;• Co-morbidities: conditions like diabetes, heart disease, or gastrointestinal disorders can impact drug absorption and metabolism;• Other Medications: drug-drug interactions can either enhance or inhibit the effects of a drug; and• Diet and Lifestyle: food intake, alcohol consumption, and smoking can influence drug absorption and metabolism.

[0008] Drug-Related Factors can include:• Formulation and Route of Administration: the form of the drug (tablet, injection, etc.) and how it is administered (oral, intravenous, etc.) can affect its absorption and bioavailability;• Chemical Properties: the solubility, stability, and molecular size of the drug can influence its absorption and distribution; and• Dosage: the amount of drug administered can impact its pharmacokinetic profile, including itsAttorney Docket No. 33194-0001 WO absorption and elimination rates.

[0009] Understanding these factors that can affect PK is thus crucial for optimizing drug therapy and ensuring that medications are both safe and effective for individual patients.

[0010] As noted above, body weight is a factor that can significantly affect the disposition of a drug in a human patient. Body weight can affect the disposition of a drug in a human patient through several key pharmacokinetic processes, including absorption, distribution, metabolism and excretion. For example, a patient’ s weight can significantly affect the volume of blood in their body. The volume of blood can affect the concentration, and thus the therapeutic effect, of the drug in the patient. Other factors such as age, sex, and overall health also can influence blood volume and thus the concentration of a drug in a patient. Body composition, including the proportion of fat and lean mass, can impact how a drug is distributed throughout the body. The liver’s capacity to metabolize drugs can also be influenced by body weight, and excess weight and obesity can lead to changes in liver enzyme activity, which may either increase or decrease the metabolism of certain drugs. These factors highlight the importance of considering body weight when determining drug dosages to ensure efficacy and minimize the risk of toxicity.SUMMARY

[0011] Although body weight can significantly affect the disposition of a drug in a human patient, it has surprisingly been discovered that body weight does not appear to be a covariant for the drug exposure of CUE-101, and thus the disposition of CUE-101 and other dimeric TMPs (DTMPs) described herein in human patients appears to be independent, or at least substantially independent, of body weight. Accordingly, this disclosure provides ready -to-use pharmaceutical compositions comprising fixed dosages of CUE-101 and other DTMPs that can provide a therapeutically effective dose while maintaining reasonable patient tolerability for the majority of patients who receive the fixed dose of CUE-101 or other DTMP. This disclosure also provides methods of treating human patients, e.g., patients who have HPV-associated cancers, including HPV16+ cancers, with such fixed dosages, whereby the amount of drug administered to the patient is not dependent on, or adjusted for, the patient’s weight. This disclosure also provides methods of treating human patients who are receiving a cellular therapy composition (e.g., CAR-T or TCR-T cells) by co-administering the cells with such fixed dosages of CUE-101 or other DTMP.

[0012] The administration of fixed dosages of CUE-101 and other DTMPs can provide theAttorney Docket No. 33194-0001 WO following advantages when compared to weight-based dosing:• Simplicity and Convenience: fixed dosing eliminates the need for complex calculations based on a patient’s weight, reducing the risk of dosing errors and making it easier for healthcare providers to administer the medication.• Cost-Effectiveness: fixed doses can be more economical, both in terms of manufacturing and administration. They simplify the production process and reduce the need for multiple dosage forms.• Standardization: fixed dosing allows for standardization in clinical practice, making it easier to compare outcomes across different patient populations and clinical trials.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIGS. 1A-1B provide amino acid sequences of P2M polypeptides.

[0014] FIGS. 1C-1F provide amino acid sequences of MHC class I heavy chain polypeptides.

[0015] FIGS. 1G-1 J provide amino acid sequences of immunoglobulin (Ig) Fc polypeptides.

[0016] FIGS. 1K-1M provide amino acid sequences of IL-2 receptor polypeptides.

[0017] FIG. IN provides the amino acid sequence of wild-type IL-2 polypeptide.

[0018] FIGS. 1O-1P provide amino acid sequences of a human papillomavirus (HPV) E6 polypeptide (FIG. 10) and an HPV E7 polypeptide (FIG. IP).

[0019] FIGS. 1Q-1S provides amino acid sequences of TMPs. Figures disclose “(GGGGS)4” as SEQ ID NO: 66, “AAAGG” as SEQ ID NO: 65, and “(GGGGS)3” as SEQ ID NO: 24.

[0020] FIGS. 1T-1V provide the amino acid sequences of variant IL-2 polypeptides.

[0021] FIG. 2 illustrates both the 2-compartment and 3-compartment models described in Example 1 that were fit to E7 concentration-time data.

[0022] FIGS. 3A-F illustrate the basic goodness of fit plots for the final preliminary population PK model described in Example 1.

[0023] FIGS. 4A-B illustrate the posterior predictive checks (PPC) of AUC (0 to infinity) and Cmax of the final pharmacokinetic model discussed in Example 1.Attorney Docket No. 33194-0001 WO

[0024] FIG. 5 illustrates the simulated AUC exposures after the administration of fixed doses (mg) and weight-based doses (mg / kg) of CUE-101 discussed in Example 1.

[0025] FIG. 6 illustrates the simulated Cmax exposures after the administration of fixed doses (mg) and weight-based doses (mg / kg) of CUE-101 discussed in Example 1.

[0026] FIG. 7 provides a comparison between a weight-based dose of 4 mg / kg and a fixed dose of 300 mg of CUE-101 in terms of the simulated AUC exposures discussed in Example 1.

[0027] FIG. 8 provides a comparison between a weight-based dose of 4 mg / kg and a fixed dose of 300 mg of CUE-101 in terms of the simulated Cmax exposures discussed in Example 1.

[0028] FIG. 9 compares the distributions of the simulated Cmax (mg / L) of the fixed dose of 150 mg and the weight-based doses of 2 and 4 mg / kg discussed in Example 2.

[0029] FIG. 10 compares the distributions of the simulated Cmax (mg / L) of the fixed doses of 150 mg, 300 mg, and weight-based dose of 2 mg / kg discussed in Example 2.

[0030] FIG. 11 compares the distributions of the simulated AUC (mg*hr / L) of the fixed dose of 150 mg and the weight-based doses of 2 and 4 mg / kg discussed in Example 2.

[0031] FIG. 12 compares the distributions of the simulated AUC (mg*hr / L) of the fixed doses of 150 mg, 300 mg, and weight-based dose of 2 mg / kg discussed in Example 2.

[0032] FIGS. 13 and 14 illustrate drug concentration-time profiles of TMPs CUE-101 and CUE- 102 administered in weight-based concentrations to rats and cynomolgus monkeys, respectively, as discussed in Example 3.

[0033] FIGS. 15A-D illustrates the drug concentration-time profiles of TMPs CUE-101 and CUE- 102 administered in weight-based concentrations to humans, as discussed in Example 3.

[0034] FIG. 16 illustrates the observed drug concentrations of CUE-101 and CUE-102 versus the individual predicted concentrations.DEFINITIONS

[0035] The term “Approved Laboratory” means a laboratory that has been certified under the Clinical Laboratory Improvement Acts (CLIA) or has been certified under a state licensure program in a state that is exempt under CLIA (currently the states of New York and Washington). Where anAttorney Docket No. 33194-0001 WO assay for PD-L1 CPS is performed outside of the U.S., an Approved Laboratory is a laboratory that is approved and / or certified under the laws of the jurisdiction where the laboratory is located.

[0036] The term “PD-L1 CPS” as used herein means a Combined Positive Score for PD-L1 expression received from any Approved Laboratory. An Approved Laboratory may or may not use an approved companion diagnostic assay to determine the PD-L1 CPS. For example, a PD-L1 CPS may be determined by an FDA-approved companion diagnostic, e.g., an approved PD-L1 IHC 22C3 pharmDx, which employs a monoclonal mouse anti-PD-Ll antibody, clone 22C3, or an approved PD-L1 IHC 28-8 pharmDx, which employs a monoclonal mouse anti-PD-Ll antibody, clone 28-8, or any other PD-L1 CPS assay that is performed by an Approved Laboratory. Alternatively, an Approved Laboratory may use a different assay and / or a different antibody to determine the PD-L1 CPS.

[0037] The term “CPI” means an antibody that acts as an immune checkpoint inhibitor by binding to an immune checkpoint protein (e g., PD-1) and blocking it from binding with its co-receptor (e.g., PD-L1).

[0038] The term “PD-(L)1 CPI” means (i) a CPI that binds to PD-1 and blocks it from binding to PD-L1, or (ii) a CPI that binds to PD-L1 and blocks it from binding to PD-1.

[0039] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein, and refer to a polymeric form of amino acids of any length, which can include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones. Furthermore, as used herein, a "polypeptide" refers to a protein that includes modifications, such as deletions, additions, and substitutions (generally conservative in nature as would be known to a person in the art) to the native sequence, as long as the protein maintains the desired activity. These modifications can be deliberate, as through site-directed mutagenesis, or can be accidental, such as through mutations of hosts that produce the proteins, or errors due to polymerase chain reaction (PCR) amplification or other recombinant DNA methods. References herein to a specific residue or residue number in a known polypeptide are understood to refer to the amino acid at that position in the wild-type polypeptide. To the extent that the sequence of the wild-type polypeptide is altered, either by addition or deletion of one or more amino acids, one of ordinary skill will understand that a reference to the specific residue or residue number will be correspondingly altered so as to refer to the same specific amino acid in the altered polypeptide, which would be understood to reside at an altered position number. For example, if an MHC classAttorney Docket No. 33194-0001 WOI polypeptide is altered by the addition of one amino acid at the N-terminus, then a reference to position 84 or a specific residue at position 84, will be understood to indicate the amino acids that are at position 85 on the altered polypeptide. Likewise, a reference herein to substitution of a specific amino acid at a specific position, e.g., Y84, is understood to refer to a substitution of an amino acid for the amino acid at position 84 in the wild-type polypeptide. A Y84C substitution is thus understood to be a substitution of Cys residue for the Tyr residue that is present in the wild-type sequence. If, e.g., the wild-type polypeptide is altered to change the amino acid at position 84 from its wild-type amino acid to an alternate amino acid, then the substitution for the amino acid at position 84 will be understood to refer to the substitution for the alternate amino acid. If in such case the polypeptide is also altered by the addition or deletion of one or more amino acids, then the reference to the substitution will be understood to refer to the substitution for the alternate amino acid at the altered position number. A reference to a “non-naturally occurring Cys residue” in a polypeptide, e.g., an MHC class I polypeptide, means that the polypeptide comprises a Cys residue in a location where there is no Cys in the corresponding wild-type polypeptide. This can be accomplished through routine protein engineering in which a cysteine is substituted for the amino acid that occurs in the wild-type sequence.

[0040] A polypeptide has a certain percent "sequence identity" to another polypeptide, meaning that, when aligned, that percentage of amino acids are the same, and in the same relative position, when comparing the two sequences. Sequence identity can be determined in a number of different ways. To determine sequence identity, sequences can be aligned using various convenient methods and computer programs (e.g., BLAST (Basic Local Alignment Search Tool), T-COFFEE, MUSCLE, MAFFT, etc.), available over the world wide web at sites including ncbi.nlm.nili.gov / BLAST, ebi.ac.uk / Tools / msa / tcoffee / , ebi.ac.uk / Tools / msa / muscle / , mafft.cbrc.jp / alignment / software / . See, e.g., Altschul et al. (1990), J. Mol. Biol. 215:403-10. Unless otherwise stated, as referred to herein, a “percent amino acid sequence identity” (or a “% amino acid sequence identity”) is determined by BLAST+2.10.0 using default parameters, which is available over the world wide web at sites including https: / / ncbiinsights.ncbi.nlm.nih.gov / 2019 / 12 / 18 / blast-2-10-0 / .

[0041] The term "conservative amino acid substitution" refers to the interchangeability in proteins of amino acid residues having similar side chains. For example, a group of amino acids having aliphatic side chains consists of glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains consists of serine and threonine; a group of amino acidsAttorney Docket No. 33194-0001 WO having amide containing side chains consisting of asparagine and glutamine; a group of amino acids having aromatic side chains consists of phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains consists of lysine, arginine, and histidine; a group of amino acids having acidic side chains consists of glutamate and aspartate; and a group of amino acids having sulfur containing side chains consists of cysteine and methionine. Exemplary conservative amino acid substitution groups are valine-leucine-isoleucine, phenyl al anine-tyrosine, lysine-arginine, alanine-valine-glycine, and asparagine-glutamine.

[0042] “ T cell” includes all types of immune cells expressing CD3, including T-helper cells (CD4+cells), cytotoxic T-cells (CD8+cells), T-regulatory cells (Treg), and NK-T cells.

[0043] The term “immunomodulatory polypeptide” (also referred to herein as a “MOD”), as used herein, means a polypeptide that specifically binds a cognate costimulatory polypeptide on a T cell, thereby providing a signal which, in addition to the primary signal provided by, for instance, binding of a T cell receptor (TCR) / CD3 complex with a major histocompatibility complex (MHC) polypeptide loaded with peptide, mediates a T cell response, including, but not limited to, proliferation, activation, differentiation, and the like.

[0044] As used herein the term “ / / / vivo” refers to any process or procedure occurring inside of the body.

[0045] As used herein the term "in vitro” refers to any process or procedure occurring outside of the body.

[0046] The terms “treatment,” “treating,” and the like are used herein to generally mean obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment” as used herein covers any treatment of a disease or symptom in a mammal, and includes: (a) preventing the disease or symptom from occurring in a subject which may or may not be predisposed to acquiring the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease or one or more symptoms associated with the disease, e.g., arresting its development; and / or (c) relieving the disease, i.e., causing regression of the disease. The therapeutic agent may be administered before, during and / or after the onset of disease or injury. The treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms ofAttorney Docket No. 33194-0001 WO the patient, is of particular interest. Such treatment is desirably performed prior to complete loss of function in the affected tissues. The subject therapy will desirably be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease.

[0047] The terms “individual,” “subject,” “host,” and “patient,” are used interchangeably herein and refer to any human subject for whom diagnosis, treatment, or therapy is desired.

[0048] Unless indicated otherwise, the term “substantially” is intended to encompass both “wholly” and “largely but not wholly.” For example, an Ig Fc that “substantially does not induce ADCC” (i.e., antibody-dependent cell cytotoxicity) means an Ig Fc that induces no ADCC at all or that largely does not induce ADCC.

[0049] As used herein, the term “about” used in connection with an amount indicates that the amount can vary by 10% of the stated amount. For example, “about 150” means an amount of from 135 to 165, and “about 300” means 270 to 330. Where about is used in the context of a range, the “about” used in reference to the lower amount of the range means that the lower amount includes an amount that is 10% lower than the lower amount of the range, and “about” used in reference to the higher amount of the range means that the higher amount includes an amount 10% higher than the higher amount of the range. For example, from about 150 to about 300 means that the range extends from 135 to 330.

[0050] It is to be understood that this disclosure is not limited to particular embodiments described, as such embodiments may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the disclosure in any way.

[0051] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.Attorney Docket No. 33194-0001 WO

[0052] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0053] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a “T- cell modulatory protein” includes a plurality of such proteins and reference to “the immunomodulatory polypeptide” includes reference to one or more immunomodulatory polypeptides and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only,” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0054] The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. For example, if the range 10-15 is disclosed, then 11, 12, 13, and 14 are also disclosed. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments of the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed.

[0055] The term “and / or” as used herein a phrase such as “A and / or B” is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used herein a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0056] It is understood that aspects and embodiments of this disclosure described herein include “comprising,” “consisting of,” and “consisting essentially of’ aspects and embodiments.

[0057] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment.Attorney Docket No. 33194-0001 WOConversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the disclosure are specifically embraced by this disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by this disclosure and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.

[0058] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that this disclosure is not entitled to antedate such publication. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.DETAILED DESCRIPTION

[0059] This disclosure provides pharmaceutical compositions comprising a fixed dose of CUE- 101 or a DTMP that comprises a peptide-MHC complex that presents an HPV-associated peptide. Such fixed doses may be used, for example, in methods of treating a patient who has HPV16- associated cancer, the methods including administering to the individual a dimeric T-cell modulatory protein (DTMP) as described herein. The amount of the CUE-lOlor DTMP in the pharmaceutical composition is in ranges of from 135 mg to 330 mg, including from 150 to 300 mg, from 135 to 165 mg, and from 165 to 270 mg, and from 270 mg to 330 mg. Included within the foregoing ranges are doses of about 150 mg, 150 mg, about 200 mg, 200 mg, about 225 mg, 225 mg, about 300 mg, and 300 mg. In some cases, the amount of CUE-101 or DTMP can be higher than 330 mg, e g., from 330 mg to 495 mg, including about 350 mg, 350 mg, about 400 mg, 400 mg, about 450 mg, and 450 mg. In some cases, the fixed dose of CUE-101 or DTMP can be lower than 150 mg, e.g., from 25 mg to 50 mg, from 50 mg to 75 mg, from 75 mg to 100 mg, from 100 mg to 125 mg, and from 125 mg to 150 mg. Included within the foregoing ranges are doses of about 25 mg, 25 mg, about 50 mg, 50 mg, about 100 mg, 100 mg, about 125 mg and 125mg.T-CELL MODULATORY POLYPEPTIDES (TMPS)

[0060] A DTMP of this disclosure is a homodimer or heterodimer that comprises two T cell modulatory proteins (TMPs), wherein each TMP comprises: i) a short polypeptide from a human papilloma virus that is associated with an HPV+ cancer (an “HPV peptide”); ii) a first majorAttorney Docket No. 33194-0001 WO histocompatibility complex (MHC) class I polypeptide that is a beta-2 microglobulin (P2M) polypeptide; iii) a second MHC class I polypeptide that is heavy chain polypeptide; iv) one or more variant IL-2 immunomodulatory polypeptides; and v) a scaffold component that is an Ig Fc polypeptide such as an IgGl Fc polypeptide. The TMP may comprise one or more independently selected peptide linkers between any two adjacent components of the TMP, e.g., between one or more of: i) the HPV peptide and the P2M polypeptide; ii) the MHC class I heavy chain polypeptide and an immunomodulatory polypeptide; iii) the MHC class I heavy chain polypeptide and an Ig Fc polypeptide; iv) an Ig Fc polypeptide and an immunomodulatory polypeptide; and v) where there is more than one immunomodulatory polypeptides in tandem, between the immunomodulatory polypeptides. As discussed below, where each TMP is a heterodimer of two polypeptides, it can contain one or more interchain disulfide bonds that link the two polypeptides, as well as one or more intrachain disulfide bonds. Where each TMP is a single-chain polypeptide, it can contain one or more intrachain disulfide bonds. As also discussed below, the HPV peptide may either be part of a fusion protein or chemically conjugated to either of the MHC class I polypeptides. Each TMP of a DTMP contains a peptide-MHC complex (pMHC) that is formed by the combination of the HPV peptide, the 2M polypeptide, and the MHC class I heavy chain polypeptide. The pMHC presents an epitope that can specifically bind to a T-cell receptor (TCR) of a T cell that can bind to an antigen expressed on an HPV+ cancer cell.

[0061] Of particular interest are TMPs comprising an HPV16 cancer-associated peptide (an “HPV16 peptide”) since a high percentage of HPV-associated cancers are HPV16+ cancers. Accordingly, while this disclosure specifically describes TMPs that comprise an HPV16 peptide, it should be understood that this disclosure also expressly includes and discloses TMPs that contain an HPV peptide other than an HPV16 peptide.TMPs in which the HPV peptide is part of a fusion protein

[0062] In some cases, the TMPs in a DTMP are single-chain polypeptides. Examples of singlechain TMPs and dimers thereof, are described in WO2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as they pertain single-chain TMP polypeptides, or dimers comprising two singlechain TMP polypeptides, is expressly incorporated herein by reference.

[0063] In some cases, the TMP is a multimeric antigen-presenting polypeptide (MAPP) or is a homodimer or heterodimer of a MAPP as described in WO2021 / 242935 (Cue Biopharma, Inc.) orAttorney Docket No. 33194-0001 WOWO2022 / 099157 (Cue Biopharma, Inc.), the disclosures of which as they pertain to MAPPs and a homodimer or heterodimer thereof, are expressly incorporated by reference.

[0064] In some cases such as in the case of CUE-101, the DTMP is a homodimer of two heterodimers. Examples of heterodimeric TMPs and DTMPs thereof are described in WO2018 / 119114 and WO2020 / 132136 (both to Cue Biopharma, Inc.), the disclosures of which as they pertain to such heterodimeric TMPs (referred to therein as “T-cell multimeric polypeptides” or “TMMPs”) and homodimer or heterodimer TMPs thereof are expressly incorporated by reference.

[0065] In some cases such as with CUE-101, the first polypeptide of a heterodimeric TMP (or of a dimeric TMP of two heterodimeric TMPs) comprises (i) a peptide from human papillomavirus (HPV), e.g., the HPV16 E7 (11-20) amino acid sequence YMLDLQPETT (SEQ ID NO:20), and (ii) a P2M polypeptide, e.g., comprising an amino acid sequence as set forth in SEQ ID NO:2 (depicted in FIG. IB, where amino acid 12 is a Cys). The second polypeptide comprises (i) two copies of a variant IL-2 polypeptide in tandem, each copy comprising an amino acid sequence having at least about 95% percent amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:21 (depicted in FIG. IT), wherein, as discussed below, the variant IL-2 polypeptides exhibits decreased or substantially no binding to IL-2Ra, thereby minimizing or substantially reducing the activation of Tregs by the IL-2 variant, and decreased binding to IL-2RP such that the IL -2 variant MOD exhibits an overall reduced affinity for IL-2R, (ii) an MHC class I heavy chain polypeptide, e.g., an MHC heavy chain polypeptide comprising an amino acid sequence having at least about 95% percent amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS:3-6 (depicted in FIGS. 1C-1F), and (iii) a Ig Fc polypeptide, e.g., an IgGl Fc polypeptide having at least about 95% percent amino acid sequence identity to the amino acid sequence set forth in SEQ ID NOV or SEQ ID NO: 10 (depicted in FIGS. II and 1J), e.g., an Ig Fc that substantially does not induce cell lysis (as discussed below) through known mutations such as the “LALA” mutations discussed below. The first polypeptide typically comprises a peptide linker that joins the HPV peptide to the P2M polypeptide, and the second polypeptide typically may comprise one or more peptide linkers joining adjacent polypeptide components of the second polypeptide.

[0066] The first and second polypeptides of each heterodimer are connected by at least one disulfide bond that spontaneously forms between the polypeptides. For example, the first and second polypeptides of a heterodimer may be joined by a disulfide bond that (i) connects a Cys residue in the P2M polypeptide to a Cys residue in the MHC class I heavy chain (e.g., a disulfide bond betweenAttorney Docket No. 33194-0001 WO the Cys residue at amino acid 12 of the 02M polypeptide and the Cys residue at amino acid 236 of the MHC class I heavy chain polypeptide). As another example, the first and second polypeptides of a heterodimer may be joined by a disulfide bond that connects (i) a Cys residue in the linker that joins the HPV peptide and the 02M polypeptide to (ii) a Cys residue in the MHC class I heavy chain polypeptide.

[0067] A disulfide bond formed between (i) a Cys amino acid in the linker between an HPV peptide and a [32M polypeptide and (ii) a Cys in the MHC class I heavy chain polypeptide may be referred to as a “linker disulfide.” A disulfide bond formed between a Cys amino acid in [32M polypeptide and a Cys in the MHC class I heavy chain polypeptide may be referred to as a “body disulfide.” A heterodimeric or single-chain TMP may comprise either or both of a linker disulfide and a body disulfide. For example, the first and second polypeptides of a heterodimer may be joined by a first disulfide bond (a body disulfide) that connects a Cys residue in the 2M polypeptide to a Cys residue in the MHC class I heavy chain (e.g., a disulfide bond between the Cys residue at amino acid 12 of the P2M polypeptide and the Cys residue at amino acid 236 of the MHC class I heavy chain polypeptide), and a second disulfide bond (a linker disulfide) that connects (i) a Cys residue in the linker (e.g., a G2C linker as discussed below) that joins the HPV peptide to the P2M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide. (Single-chain TMPs comprising a linker disulfide are discussed below.) The two heterodimers of the homodimer are joined to each other by one or more disulfide bonds (typically two disulfide bonds) that spontaneously form to join the Ig Fc polypeptide of one heterodimer to the Ig Fc polypeptide of the other heterodimer.CUE-101

[0068] As discussed above, CUE-101 is a homodimer comprised of two identical heterodimers. The first polypeptide of each heterodimer comprises, in order from N-terminus to C- terminus: (i) an HPV16 E7 epitope comprising amino acid sequence YMLDLQPETT (SEQ ID NO:20); (ii) a linker comprising amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:24); and (iii) a P2-microglobulin (P2M) polypeptide comprising the amino acid sequence of SEQ ID NO:2. The second polypeptide, which comprises two variant IL-2 polypeptides, a class I MHC heavy chain polypeptide, and a variant IgGl Fc polypeptide, has the amino acid sequence as set forth in FIG. 25 of WO / 2018 / 119114, the contents of which is expressly incorporated herein by reference. The first polypeptide and the second polypeptide of each heterodimer are covalently linked to oneAttorney Docket No. 33194-0001 WO another via a disulfide bond between a Cys residue at amino acid 12 of the 02M polypeptide and a Cys residue at amino acid 236 of the class I MHC heavy chain polypeptide. The two heterodimers are then joined to each other by two disulfide bonds that join cysteines in the IgGl Fc polypeptide of one heterodimer to cysteines in the IgGl Fc polypeptide of the other heterodimer. The disclosure of WO / 2018 / 119114 as it pertains to this homodimer of two heterodimers is expressly incorporated herein by reference. It is noted that the lysine residue at the C-terminus of the IgGl Fc may be present or may be absent as a result of the manufacturing process or may be intentionally omitted.TMPs in which the HPV peptide is chemically conjugated

[0069] Unlike the above-described TMPs in which the HPV peptide is part of a fusion protein with the P2M polypeptide (in the case of heterodimeric TMPs) or both the P2M polypeptide and the MHC class I polypeptide (in the case of single-chain TMPs), in some cases the TMP may comprise an HPV peptide (e.g., an HPV16 peptide) that is chemically conjugated to a chemical conjugation site in one of the MHC class polypeptides, i.e., the P2M polypeptide or MHC class I heavy chain polypeptide. For example, the HPV peptide may be chemically conjugated to a chemical conjugation site (e.g., a cysteine) that is provided in the [32M polypeptide. The stabilized MHC and chemically conjugated peptide form a pMHC that allows the protein to selectively modulate T cells that can bind to and kill HPV-associated cancer cells. In some cases, such TMP’s comprising chemically conjugated HPV peptides comprise heterodimeric polypeptides to which the HPV peptide is chemically conjugated, or dimeric TMPs comprising two of such heterodimeric polypeptides. See, e.g., W02019 / 051127 and WO2020 / 132368 (Cue Biopharma, Inc ), the disclosures of which are expressly incorporated herein by reference. In some cases, such TMP’s comprising chemically conjugated HPV peptides are single-chain polypeptides to which the HPV peptide is chemically conjugated, or dimeric TMPs comprising two of such single-chain polypeptides. See, e g., W02022 / 015880 (Cue Biopharma, Inc.), the disclosure of which is expressly incorporated by reference. Such TMPs comprising chemically conjugated HPV peptides may comprise one or more body disulfides but typically will not comprise a linker disulfide.HPV PEPTIDES

[0070] As noted above, a TMP comprises a short HPV polypeptide (referred to herein as an HPV peptide) that, together with the MHC polypeptides, can form a complex, i.e. a pMHC, that presentsAttorney Docket No. 33194-0001 WO an epitope that can specifically bind to a TCR of a target T cell that can bind to and kill HPV- associated cancer cells.

[0071] An HPV peptide can have a length of at least 4 amino acids, e.g., from 4-20 aa (e.g., 4 amino acids (aa), 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, 10 aa, 11 aa, 12 aa, 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19 aa or 20 aa), including a range of from 6-15 aa, 8-12 aa, 8-14 aa, 8-16 aa, 8-10 aa, 9-11 aa, 5- 10 aa, 10-15 aa, and 15-20 aa in length. In some cases, the peptide is 8, 9, 10, 11 or 12 amino acids in length.

[0072] In some cases, an HPV peptide suitable for inclusion in a pMHC can be a peptide of an HPV E6 polypeptide or an HPV E7 polypeptide. The HPV epitope can be an epitope of HPV of any of a variety of genotypes, including, e.g., HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, HPV68, HPV73, or HPV82. In some cases, the peptide is a peptide of an HPV E6 peptide (FIG. 10; SEQ ID NO: 15). In some cases, the peptide is a peptide of an HPV E7 polypeptide (FIG. IP; SEQ ID NO: 16). In some cases, an HPV peptide is a peptide of from 4-20 aa, e.g., 6-15 aa, 8-12 aa, 8-10 aa, 8-12 aa, 9-11 aa, 5-10 aa, 10-15 aa, or 15- 20 aa in length of an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the HPV E6 amino acid sequence (FIG. 10; SEQ ID NO: 15) or the HPV E7 amino acid sequence (FIG. IP; SEQ ID NO: 16).

[0073] Examples of HPV E6 peptides suitable for inclusion in a TMP include, but are not limited to, E6 18-26 (KLPQLCTEL; SEQ ID NO:25); E6 26-34 (LQTTIHDII; SEQ ID NO:26); E6 49-57 (VYDFAFRDL; SEQ ID NO:27); E6 52-60 (FAFRDLCIV; SEQ ID NO:28); E6 75-83 (KFYSKISEY; SEQ ID NO:29); and E6 80-88 (ISEYRHYCY; SEQ ID NO:30).

[0074] Examples of HPV E7 peptides suitable for inclusion in a TMP include, but are not limited to, E7 7-15 (TLHEYMLDL; SEQ ID NO:31); E7 11 -19 (YMLDLQPET; SEQ ID NO:32); E7 11- 20 (YMLDLQPETT; SEQ ID NO:20); E7 44-52 (QAEPDRAHY; SEQ ID NO:33); E7 49-57 (RAHYNIVTF (SEQ ID NO:34); E7 61-69 (CDSTLRLCV; SEQ ID NO:35); and E7 67-76 (LCVQSTHVDI; SEQ ID NO:36); E7 82-90 (LLMGTLGIV; SEQ ID NO:37); E7 86-93 (TLGIVCPI; SEQ ID NO: 38); and E7 92-93 (LLMGTLGIVCPI; SEQ ID NO 39).

[0075] In some cases, a suitable HPV peptide for inclusion in a TMP is an HPV E6 peptide that binds HLA-A24 (e.g., is an HLA-A2401 -restricted epitope). Non-limiting examples include: VYDFAFRDL (SEQ ID NO:27) CYSLYGTTL (SEQ ID NO:40); EYRHYCYSL (SEQ ID NO:41);Attorney Docket No. 33194-0001 WOKLPQLCTEL (SEQ ID NO:25); DPQERPRKL (SEQ ID NO:42); HYCYSLYGT (SEQ ID NO:43); DFAFRDLCI (SEQ ID NO:44); LYGTTLEQQY (SEQ ID NO:45); HYCYSLYGTT (SEQ ID NO:46); EVYDFAFRDL (SEQ ID NO:47); EYRHYCYSLY SEQ ID NO:48); VYDFAFRDLC (SEQ ID NO:49); YCYSIYGTTL (SEQ ID NO:50); VYCKTVLEL (SEQ ID N0:51); VYGDTLEKL (SEQ ID NO:52); and LTNTGLYNLL (SEQ ID NO:53).

[0076] In some cases, a suitable HPV peptide for inclusion in a TMP is selected from: DLQPETTDL (SEQ ID NO:54); TLHEYMLDL (SEQ ID NO:31); TPTLHEYML (SEQ ID NO:55); RAHYNIVTF (SEQ ID NO:34); GTLGIVCPI (SEQ ID NO:56); EPDRAHYNI (SEQ ID NO:57); QLFLNTLSF (SEQ ID NO:58); FQQLFLNTL (SEQ ID NO: 59); and AFQQLFLNTL (SEQ ID NO:60).

[0077] In some cases, a suitable HPV peptide presents an HLA-A*2401 -restricted epitope. Nonlimiting examples of HPV peptides presenting an HLA-A*2401 -restricted epitope include: VYDFAFRDL (SEQ ID NO:27); RAHYNIVTF (SEQ ID NO:34); CDSTLRLCV (SEQ ID NO:35); and LCVQSTHVDI (SEQ ID NO: 36).MHC POLYPEPTIDESP2M Polypeptides

[0078] The P2M polypeptide present in the TMP can comprise an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the 02M amino acid sequence of SEQ ID NO: 1 depicted in FIG. 1 A. In some cases, a 02M polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the P2M amino acid sequence of SEQ ID NO:2 depicted in FIG. IB, where amino acid 12 is a Cys. In some cases, a P2M polypeptide comprises the amino acid sequence of SEQ ID NO:2 depicted in FIG. IB.MHC class I heavy chain polypeptides

[0079] As noted above, a TMP comprises an MHC class I heavy chain polypeptide. In some cases, the MHC class I heavy chain is a heavy chain from an HLA-A, -B, -C, -E, -F, or -G allele. An “MHC class I heavy chain polypeptide” that is found in a human may also be referred to as a human leukocyte antigen (HLA) class I heavy chain polypeptide. In some cases, the MHC class I heavy chain is a heavy chain from HLA-A*0101, A*0201, A*0301, A*1101, A*2301, A*2402, A*2407, A*33O3, and / or A*3401. In some cases, the MHC class I heavy chain is a heavy chain from HLA-Attorney Docket No. 33194-0001 WOB*0702, B*0801, B*1502, B*3802, B*4001, B*4601, and / orB*5301. In some cases, the MHC class I heavy chain is a heavy chain from C*0102, C*0303, C*0304, C*0401, C*0602, C*0701, C*702, C*0801, and / or C*1502. The amino acid sequences of these MHC class I heavy chain polypeptides are known, see, e.g., FIGS. 3A-3E, 4A-4E, 5A-5E, 6A-6E, 7A-7B, 8A-8B, and 9A-9B of WO2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as it pertains to those figures is expressly incorporated herein by reference. In some cases, the MHC class I heavy chain is a heavy chain from HLA-E*0101 (HLA-E*01:01:01:01), HLA-E*01:03(HLA-E*01:03:01:01), HLA- E*01:04, HLA-E*01:05, HLA-E*01:06, HLA-E*01:07, HLA-E*01:09, and HLA-E*01:10. Two HLA-E alleles that have a significant prevalence in humans are HLA-E*0101 (HLA-E*01 :01 : 01 : 01 ) and HLA-E*01 :03(HLA-E*01:03:01 :01). The amino acid sequences of these HLA-E alleles are likewise known. See, e.g., FIG. 10 of WO2022 / 197970 (Cue Biopharma, Inc.), which provides a consensus sequence for various HLA-E alleles. The disclosure of WO2022 / 197970 as it pertains to FIG. 10, is expressly incorporated herein by reference.

[0080] In some cases, the TMP comprises an MHC class I HLA-A allele heavy chain. In some cases, the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the HLA-A heavy chain amino acid sequence of SEQ ID NO:3 depicted in FIG. 1C.

[0081] In some cases, where the TMP comprises a heterodimer, the MHC class I heavy chain polypeptide of the second polypeptide comprises an Ala at position 84 and a Cys at position 236. Thus, e.g., in some cases, the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the HLA-A heavy chain amino acid sequence of SEQ ID NO:4 depicted in FIG. ID, where amino acid 84 is an Ala and amino acid 236 is a Cys.

[0082] In some cases, where the TMP comprises a heterodimer, the MHC class I heavy chain polypeptide of the second polypeptide comprises a Cys at position 84 and a Cys at position 236. Thus, e.g., in some cases, the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the HLA-A heavy chain amino acid sequence of SEQ ID NO:5 depicted in FIG. IE, where amino acid 84 is a Cys and amino acid 236 is a Cys.Attorney Docket No. 33194-0001 WO

[0083] In some cases, where the TMP comprises a heterodimer, the MHC class I heavy chain polypeptide of the second polypeptide comprises an Ala at position 84, a Cys at position 139, and a Cys at position 236. Thus, e.g., in some cases, the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the HLA-A heavy chain amino acid sequence of SEQ ID NO:6 depicted in FIG. IF, where amino acid 84 is an Ala, amino acid 139 is a Cys, and amino acid 236 is a Cys.

[0084] Where the TMP is a single-chain TMP (or a dimeric TMP, e.g., homodimer, of singlechain TMPs), the TMP may comprise one or more spontaneously formed intrachain disulfide bonds, including either or both of a linker disulfide and one or more body disulfides. A linker disulfide may be formed between: (i) a Cys present in a peptide linker interposed between the HPV peptide and the 02M polypeptide (e.g., a G2C linker), and (ii) a Cys is substituted for one of the amino acids in the peptide binding groove of the MHC class I heavy chain polypeptide, e.g. a Cys substituted at position 84 or a Cys substituted at any one of amino acids 135-143 (e.g., at position 139), based on the numbering of the MHC class I heavy chain polypeptide depicted in FIG. IF (SEQ ID NO:6). Where such a linker disulfide is formed with a Cys substituted at any one of amino acids 135-143, e.g., at position 139, then the amino acid at position 84 is other than a Cys, e.g., is Ala, Gly, Vai or Tyr. Conversely, where such a linker disulfide is formed with a Cys substituted at position 84, then amino acids 135-143, e.g., at position 139, are other than Cys residues.SCAFFOLD POLYPEPTIDES

[0085] As noted above, a TMP typically comprises a scaffold polypeptide such as an Ig Fc polypeptide or a non-Ig Fc polypeptide.

[0086] An Ig Fc polypeptide of a TMP can be a human IgGl Fc, a human IgG2 Fc, a human IgG3 Fc, a human IgG4 Fc, etc., or a variant of a wild-type Ig Fc polypeptide. Variants include naturally occurring variants, non-naturally occurring variants, and combinations thereof. For example, the Ig Fc can be a variant of a Fc polypeptide such as a human IgGl Fc, which variant has a reduced or substantially eliminated ability to effect complement-dependent cytotoxicity (CDC) or antibodydependent cell-mediated cytotoxicity (ADCC). Such variants are well known.Attomey Docket No. 3o 194-0001 WO

[0087] In some cases, e.g., where TMP comprises a heterodimer of first and second polypeptides, the Ig Fc may be at the C-terminus of the second polypeptide. In such cases, the Ig Fc polypeptide optionally does not comprise a C-terminal Lys.

[0088] In some cases, the Fc polypeptide present in a TMP is an IgGl Fc polypeptide, or a variant of an IgGl Fc polypeptide. For example, in some cases, the IgGl Fc polypeptide present in a TMP comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the human IgGl Fc polypeptide amino acid sequence of SEQ ID NO:7 depicted in FIG. IG, or the human IgGl Fc polypeptide amino acid sequence: of SEQ ID NO: 8 depicted in FIG. 1H. In such cases, the Ig Fc polypeptide optionally does not comprise a C-terminal Lys.

[0089] In some cases, the Ig Fc polypeptide present in a TMP comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the Ig Fc polypeptide amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO: 10 (and depicted in FIG. II or FIG. 1J), where amino acid 14 is an Ala and amino acid 15 is an Ala. (As discussed below, substitutions of Ala for Leu at amino acids 14 and 15 are known as the “LALA” mutations.) Thus, in some cases, the Ig Fc polypeptide present in a TMP comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the Ig Fc amino acid sequence of SEQ ID NO:9 depicted in FIG. II, where amino acid 14 is an Ala and amino acid 15 is an Ala, and where the Ig Fc omits a C-terminal Lys. In some cases, the Ig Fc polypeptide present in a TMP comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the Ig Fc amino acid sequence of SEQ ID NO: 10 depicted in FIG. 1 J, where amino acid 14 is an Ala and amino acid 15 is an Ala, and where the Ig Fc comprises a C-terminal Lys.IMMUNOMODULATORY POLYPEPTIDES

[0090] As noted above, a TMP comprises one or more immunomodulatory polypeptides (“MODs”). In some cases, a MOD present in the TMP is a wild-type (“wt”) MOD. In other cases, a MOD present in a TMP is a variant of a wt MOD that has reduced affinity for a co-MOD compared to the affinity of a corresponding wild-type MOD for the co-MOD. Suitable MODs that exhibit reduced affinity for a co-MOD can have from 1 amino acid (aa) to 20 aa differences from a wild-Attorney Docket No. 33194-0001 WO type MOD. For example, in some cases, a variant MOD present in a TMP differs in amino acid sequence by 1 aa, 2 aa, 3 aa, 4 aa, 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, or 10 aa, from a corresponding wildtype MOD. As another example, in some cases, a variant MOD present in a TMP differs in amino acid sequence by 11 aa, 12 aa, 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19 aa, or 20 aa, from a corresponding wild-type MOD.

[0091] Of interest in this disclosure are MODs that promote activation and / or proliferation of the T cell to which the TMP binds. Examples of such MODs include IL-2, CD80, CD86, and 4-1BBL polypeptides.

[0092] Wild-type immunomodulatory polypeptides and variants, including reduced affinity variants, such as CD80, CD86, 4-1BBL, and IL-2 are described in the published literature, e.g., published PCT application WO2020 / 132138A1 and W02019 / 051091 (Cue Biopharma, Inc.), the disclosures of which as they pertain to MODs and specific variant MODs of CD80, CD86, 4-1BBL, and IL-2 are expressly incorporated herein by reference.

[0093] Of particular interest are MODs that are variants of the cytokine IL-2. Wild-type IL-2 binds to IL-2 receptor (IL-2R) on the surface of a T cell. Wild-type IL-2 has a strong affinity for IL-2R and will bind to activate most or substantially all CD8+ T cells. For this reason, synthetic forms of wild type IL-2 such as the drug Aldesleukin (trade name Proleukin®) are known to have severe side-effects when administered to humans for the treatment of cancer because the IL-2 indiscriminately activates both target and non-target T cells.

[0094] An IL-2 receptor is a heterotrimeric polypeptide comprising an alpha chain (IL-2Ra; also referred to as CD25), a beta chain (IL-2RP; also referred to as CD122: and a gamma chain (IL-2Ry; also referred to as CD132). Amino acid sequences of human IL-2, human IL-2Ra, IL2RP, and IL- 2Ry are known. See, e g., published PCT applications WO2020 / 132138A1 and WO2019 / 051091, discussed above. For example, a wild-type IL-2 polypeptide can have the amino acid sequence depicted in FIG. IN (SEQ ID NO: 14). Amino acid sequences of human IL-2Ra, human IL-2RP, and human IL-2RY are depicted in FIG. IK, IL, and IM, respectively, where the mature form of IL- 2Ra is amino acids 22-272 of the amino acid sequence depicted in FIG. IK, the mature form of IL- 2RP is amino acids 27-551 of the amino acid sequence depicted in FIG. IL, and the mature form of IL-2RY is amino acids 23-369 of the amino acid sequence depicted in FIG. IM.Attorney Docket No. 33194-0001 WO

[0095] In some cases, an IL-2 variant MOD of this disclosure exhibits decreased binding to IL- 2Ru, thereby minimizing or substantially reducing the activation of Tregs by the IL-2 variant. Alternatively, or additionally, in some cases, an IL-2 variant MOD of this disclosure exhibits decreased binding to IL-2RP and / or ZL-2Ry such that the IL-2 variant MOD exhibits an overall reduced affinity for IL-2R. In some cases, an IL-2 variant MOD of this disclosure exhibits both properties, i.e., it exhibits decreased or substantially no binding to IL-2Ra, and also exhibits decreased binding to IL-2R.P and / or IL-2Ry such that the IL-2 variant polypeptide exhibits an overall reduced affinity for IL-2R. For example, IL-2 variants having substitutions at H16 and F42, which are the substitutions in each of the four variant IL-2 polypeptides of each CUE-101 molecule, have shown decreased binding to IL-2Ra and IL-2Rp. See, Quayle et al., Clin Cancer Res; 26(8) April 15, 2020, which discloses that the binding affinity of an IL-2 polypeptide with H16A and F42A substitutions for human IL-2Ra and IL-2RP was decreased 110- and 3-fold, respectively, compared with wild-type IL2 binding, predominantly due to a faster off-rate for each of these interactions. TMPs such as CUE-101 comprising such variants that exhibit decreased binding to IL-2Ra and IL- 2R13, have shown the ability to preferentially bind to and activate IL-2 receptors on T cells that contain the target TCR that is specific for the epitope presented by the pMHC of the TMP, and are thus less likely to deliver IL-2 to non-target T cells, i.e., T cells that do not contain a TCR that specifically binds the epitope presented by the pMHC of the TMP. In such cases, the binding of the IL-2 variant MOD to its costimulatory polypeptide on the T cell is substantially driven by the binding of the MHC-epitope moiety rather than by the binding of the variant IL-2 polypeptide to IL-2R receptors on the T cell.

[0096] Suitable IL-2 variant MODs thus include a polypeptide that comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to the wild-type IL -2 amino acid sequence depicted in FIG. IN (SEQ ID NO: 14); and that have one or more amino acid differences from the wild-type IL-2 amino acid sequence depicted in FIG. IN. In some cases, such a variant IL-2 polypeptide of this disclosure exhibits reduced binding affinity to IL-2R, compared to the binding affinity of an IL-2 polypeptide comprising the wild-type IL-2 amino acid sequence depicted in FIG. IN. For example, in some cases, a variant IL-2 polypeptide binds IL-2R with a binding affinity that Is at least 10% less, at least 15% less, at least 20% less, at least 25%, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, at least 55% less, at least 60% less, at least 65% less, at least 70% less, at least 75% less, at least 80% less, at least 85% less, at least 90% less, at least 95% less, orAttorney Docket No. 33194-0001 WO more than 95% less, than the binding affinity of an IL-2 polypeptide comprising the wild-type IL-2 amino acid sequence depicted in FIG. IN for an IL-2R (e.g., an IL-2R comprising polypeptides comprising the amino acid sequences depicted in FIGS. 1K-1M, e.g., the mature forms of the amino acid sequences depicted in FIGS. 1K-1M), when assayed under the same conditions.

[0097] Exemplary combinations of mutations that reduce binding of an IL-2 variant polypeptide to IL-2Ra and IL-2RP are provided in Table 5 of WO2023 / 097188 (Cue Biopharma, Inc.), the disclosure of which as it pertains to Table 5 is expressly incorporated herein by reference.

[0098] In some cases, a suitable variant IL-2 polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO:21 depicted in FIG. IT, where Xi is an amino acid other than His, and where X2 is an amino acid other than Phe. In some cases, i) Xi is Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Vai; and ii) X2 is Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, He, Leu, Lys, Met, Pro, Ser, Thr, Trp, Tyr, or Vai. In some cases, Xi is Ala and X2 is Ala. In some cases, Xi is Thr and X2 is Ala. In some cases, Xi is Asp and X2 is Ala. In some cases, Xi is Glu and X2 is Ala.

[0099] In some cases, a suitable variant IL-2 polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO:22 depicted in FIG. 1U, i.e., the variant IL-2 polypeptide has the amino acid sequence of wild-type IL-2 but with H16A and F42A substitutions (shown in bold). Alternatively, the foregoing sequence, but with substitutions other than Ala at H16 and / or F42 may be employed, e.g., H16T may be employed instead of H16A. In some cases, a variant IL-2 polypeptide present in a TMP comprises the amino acid sequence of SEQ ID NO:22. In some cases, a variant IL-2 polypeptide present in a TMP comprises the amino acid sequence of SEQ ID NO:23 depicted in FIG. IV. In some cases, a TMP comprises two copies of such a variant IL-2 polypeptide. Where a TMP comprises two copies of a variant IL-2 polypeptide, the two copies may be in tandem. Where a TMP comprises two copies of a variant IL-2 polypeptide, and where the two copies are in tandem, in some cases, the TMP comprises a peptide linker between the two copies.Attorney Docket No. 33194-0001 WOLINKERS

[0100] A TMP of this disclosure can include one or more polypeptide linkers (referred to as peptide linkers herein) interposed between any two polypeptide components of the TMP. Such peptide linkers are well known. See, e.g., WO2020 / 132136 (Cue Biopharma, Inc.). For example, one or more linkers may be interposed between one or more of: i) an HPV peptide and a P2M polypeptide; ii) an MHC class I heavy chain polypeptide and an Ig Fc polypeptide; iii) an MHC class I heavy chain polypeptide and an immunomodulatory polypeptide; iv) an Ig Fc polypeptide and an immunomodulatory polypeptide; and v) where a TMP comprises two immunomodulatory polypeptides in tandem, between the two immunomodulatory polypeptides.

[0101] Linkers may be a flexible peptide linker, including a short flexible peptide linker, or a rigid peptide linker. Such linkers are disclosed in WO2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as it pertains to such peptides is expressly incorporated herein by reference, including specifically, but not limited to, paragraphs

[0188] -

[0196] ,

[0102] As noted above, the linker between an HPV peptide and a 02M polypeptide may comprise a single Cys residue that can form a disulfide bond with a Cys in the MHC class I heavy chain polypeptide. Such Cys-containing linkers are disclosed in WO2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as it pertains to such peptide linkers is expressly incorporated herein by reference, including specifically, but not limited to, paragraphs

[0202] -

[0207] , Where the TMP comprises a heterodimer, the Cys in the linker can form a disulfide bond with a Cys in the MHC class I heavy chain polypeptide in the second polypeptide. Where the TMP comprises a single-chain polypeptide, the Cys in the linker can form an intrachain disulfide bond with a Cys in the MHC class I heavy chain polypeptide, e g., with a Cys at position 84 or a Cys at one of positions 135-143, e.g., at position 139.HETERODIMERIC TMPS

[0103] As noted above, in some cases, the TMP is a heterodimer, or is a TMP comprising a dimer (a homodimer or a heterodimer) of two heterodimers. The components of the TMP can be arranged in any of a variety of configurations. See, e.g., FIGS. 1A-1F, 2A-2F, 14A-14D, 15A-15C, and 16 of WO2020 / 132136 (Cue Biopharma, Inc.), the disclosure of which as it pertains to such figures and the disclosure of configurations of heterodimeric TMPs, and homodimers and heterodimers of such heterodimeric TMPs, is expressly incorporated herein by reference.Attorney Docket No. 33194-0001 WOSINGLE-CHAIN TMPS

[0104] As noted above, in some cases, a TMP is a single-chain polypeptide. The components of the single-chain TMP can be arranged in any of a variety of configurations. See, e.g., FIGS. 12 and 13 of WO2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as it pertains to such figures and the disclosure of configurations of single-chain TMPs, and homodimers and heterodimers of such single-chain TMPs, is expressly incorporated herein by reference.

[0105] A single-chain TMP comprises: i) an HPV peptide; ii) an optional peptide linker; iii) a P2M polypeptide; iv) an optional peptide linker; v) an MHC class I heavy chain polypeptide; vi) an optional peptide linker; vii) an Ig Fc polypeptide; viii) an optional peptide linker; and ix) one or more immunomodulatory polypeptides (where, if the TMP comprises two MODs in tandem, the MODs may be separated by a peptide linker). In some cases, the TMP comprises a Cys-containing peptide linker between the HPV peptide and the 02M polypeptide, and the TMP comprises an intrachain disulfide bond (i.e., a linker disulfide) between the Cys present in the peptide linker and a Cys in the MHC class I heavy chain polypeptide. In some cases, the single-chain TMP comprises an intrachain disulfide bond (i.e., a body disulfide) formed between a Cys residue in the P2M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide. In some cases, the single-chain TMP comprises both a linker disulfide and one or more body disulfides.INTERCHAIN AND INTRACHAIN DISULFIDE BONDS

[0106] As discussed above, the first and the second polypeptide of a heterodimeric TMP can be covalently linked to one another by one or more disulfide bonds, e.g., a linker disulfide and / or one or more body disulfides. Where a TMP is a single-chain polypeptide, the single-chain TMP can comprise one or more intrachain disulfide bonds, e.g., a linker disulfide and / or one or more body disulfides.

[0107] In some cases, the first and the second polypeptides of a heterodimeric TMP are covalently linked to one another by a single disulfide bond. In some cases, the single disulfide bond is a body disulfide between a Cys in the P2M polypeptide and a Cys in the MHC class I heavy chain polypeptide. In some cases, the Cys in the P2M polypeptide is amino acid 12 of the P2M polypeptide. In some cases, the Cys in the MHC class I heavy chain polypeptide is at amino acid 236. In some cases, the first and the second polypeptides of a heterodimeric TMP are covalently linked to one another by a linker disulfide bond between: i) a Cys in the peptide linker between theAttorney Docket No. 33194-0001 WOHPV peptide and the P2M polypeptide; and ii) a Cys in the MHC class I heavy chain polypeptide. In some cases, the first and the second polypeptides of a heterodimeric TMP are covalently linked to one another by at least a first and second disulfide bond, where the first disulfide bond is a body disulfide and the second disulfide is a linker disulfide. In some cases where the TMP comprises a linker disulfide, the peptide linker between the HPV peptide and the P2M polypeptide comprises the sequence CGGGS(GGGGS)n (SEQ ID NO: 61), GCGGS(GGGGS)n (SEQ ID NO 62), or GGCGS(GGGGS)n (SEQ ID NO:63), wherein n is an integer from 1-10. In some cases, the second disulfide bond is formed between: i) the Cys in the peptide linker between the HPV peptide and the P2M polypeptide; and ii) a Cys at amino acid 84 of the MHC class I heavy chain polypeptide. In some cases, the second disulfide bond is formed between the Cys in the peptide linker and a Cys at any one of amino acids 135-143 of the MHC class I heavy chain polypeptide. In some cases, the second disulfide bond is formed between: i) the Cys in the peptide linker between the HPV peptide and the P2M polypeptide; and ii) a Cys at amino acid 139 of the MHC class I heavy chain polypeptide.

[0108] In some cases, a single-chain TMP includes a single intrachain disulfide bond. In some cases, the single disulfide bond is between a Cys in the P2M polypeptide and a Cys in the MHC class I heavy chain polypeptide. In some cases, the Cys in the 2M polypeptide is amino acid 12 of the P2M polypeptide. In some cases, the Cys in the MHC class I heavy chain polypeptide is at amino acid 236. In some cases, a single-chain TMP includes 2 intrachain disulfide bonds. In some cases, the second disulfide bond is between: i) a Cys in the peptide linker between the HPV peptide and the P2M polypeptide; and ii) a Cys in the MHC class I heavy chain polypeptide. In some cases, the peptide linker between the HPV peptide and the P2M polypeptide comprises the sequence CGGGS(GGGGS)n (SEQ ID NO:61), GCGGS(GGGGS)n (SEQ ID NO:62), or GGCGS(GGGGS)n (SEQ ID NO:63), wherein n is an integer from 1-10. In some cases, the second disulfide bond is formed between: i) the Cys in the peptide linker between the HPV peptide and the P2M polypeptide; and ii) a Cys at amino acid 84 of the MHC class I heavy chain polypeptide. In some cases, the second disulfide bond is formed between the Cys in the peptide linker and a Cys at any one of amino acids 135-143 of the MHC class I heavy chain polypeptide. In some cases, the second disulfide bond is formed between: i) the Cys in the peptide linker between the HPV peptide and the 02M polypeptide; and ii) a Cys at amino acid 139 of the MHC class I heavy chain polypeptide.Attorney Docket No. 33194-0001 WOEXEMPLARY TMPS

[0109] As discussed above, a TMP can be, and often will be, a dimer of two TMPs, i.e., either a homodimer or a heterodimer. This disclosure thus provides DTMPs comprising two TMPs that are disulfide bonded together. The TMPs in DTMP can be linked by one or more (typically two) disulfide bonds between an Ig Fc polypeptide in the first TMP and an Ig Fc polypeptide in the second TMP. Two TMPs typically will self-assemble into a DTMP by spontaneously forming one or more (typically two) disulfide bonds with the Ig Fc polypeptide of another TMP. Thus, e.g., the Ig Fc polypeptides in the first TMP and the second TMP can be linked to one another by one or more (typically two) disulfide bonds.

[0110] In many cases, the two TMPs in a DTMP will be identical to one another in amino acid sequence and comprise Ig Fc polypeptides that spontaneously form one or more (typically two) disulfide bonds, thereby forming a DTMP that is a homodimer. Alternatively, a DTMP may be a heterodimer of two different TMPs. In such case, the Ig Fc polypeptides of each TMP can comprise interspecific dimerization sequences, e.g., “Knob-in-Hole” sequences that permit two different TMPs to selectively dimerize. Such interspecific dimerization sequences are disclosed in WO2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as it pertains to interspecific dimerization sequences (including but not limited to

[0212] -

[0213] ) is expressly incorporated herein by reference. Interspecific dimerization sequences also may be employed to enable TMPs to be linked to non-TMP molecules that can provide additional functionality to the TMP. For example, TMPs can be linked to molecules that comprise polypeptides (e g., antibodies or binding fragments thereof such as scFvs) that bind to cancer-associated antigens (e.g., an HPV antigen), thereby enabling the TMP to localize to tissues comprising the cancer-associated antigen. Additionally, although both TMPs of a DTMP typically will comprise the same pMHC, interspecific dimerization sequences enable the manufacture of DTMPs that are heterodimers of two TMPs, wherein the two TMPs comprise different HPV peptides. Further, through the use of interspecific dimerization sequences, a DTMP can be a heterodimer of two TMPs, wherein only one of the TMPs comprises a pMHC having an HPV peptide, and the other TMP comprises pMHC having a non-HPV peptide.

[0111] TMP dimers include homodimers and heterodimers of heterodimeric TMPs. See, e.g., WO2018 / 119114 and WO2020 / 132136 (both to Cue Biopharma, Inc.), the disclosures of which as they pertain to such TMP dimers (referred to therein as “T-cell multimeric polypeptides”) is expressly incorporated by reference.Attorney Docket No. 33194-0001 WO

[0112] As discussed above, DTMPs also include homodimers and heterodimers of single-chain TMPs. See, e.g., WO2022 / 197970 (Cue Biopharma, Inc.), the disclosure of which as it pertains to such TMP dimers (including but not limited to

[0208] -

[0217] ) is expressly incorporated herein by reference.

[0113] As discussed above, the DTMPs also include heterodimers and homodimers of TMPs that are in a multimeric antigen-presenting polypeptides (MAPPs) as described in WO2021 / 242935 (Cue Biopharma, Inc.) or WO2022 / 099157 (Cue Biopharma, Inc.), the disclosures of which as they pertain to dimers of MAPPS are expressly incorporated by reference.

[0114] DTMPs also can include heterodimers and homodimers of single-chain and heterodimeric TMPs that comprise a chemically conjugated peptide. See, e.g., W02019 / 051127, WO2020 / 132368, and W02022 / 015880 (Cue Biopharma, Inc.), the disclosures of which as they pertain to dimeric TMPs are expressly incorporated by reference.

[0115] In some cases, each TMP of a DTMP comprises a heterodimer comprising: a) a first polypeptide comprising, in order from N-terminus to C-terminus: i) an HPV peptide; ii) a peptide linker; and iii) a 02M polypeptide; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) a first immunomodulatory polypeptide; ii) a peptide linker; iii) a second immunomodulatory polypeptide; iv) an MHC class I heavy chain polypeptide; v) a peptide linker; and vi) an Ig Fc polypeptide.

[0116] In some cases, the HPV peptide is an HPV16 E7 peptide. In some cases, the HPV peptide is an HPV16 E6 peptide. In some cases, the HPV16 peptide has the amino acid sequence: YMLDLQPETT (SEQ ID NO:20).

[0117] In some cases, the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO:4 in FIG. ID. In some cases, amino acid 84 is an Ala and amino acid 236 is a Cys.

[0118] In some cases, the P2M polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO:2 in FIG. IB. In some cases, amino acid 12 is a Cys.

[0119] In some cases, each TMP of a DTMP comprises either one or two copies of a variant IL-2 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, atAttorney Docket No. 33194-0001 WO least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO:21 in FIG. IT, where Xi is other than His, e.g., Ala, Thr, Glu or Asp; and X2 is other than Phe, e.g., Ala. In some cases, amino acid 16 is an Ala and amino acid 42 is an Ala.

[0120] In some cases, e.g., where the Ig Fc is on the C-terminus of the second polypeptide of a heterodimeric TMP, the Ig Fc polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 9 in FIG. II. In some cases, amino acids 14 and 15 are both Ala, and the Ig Fc polypeptide optionally does not comprise a Lys at the C-terminus.

[0121] In some cases, including cases where the Ig Fc is on the C-terminus of the second polypeptide of a heterodimeric TMP, the Ig Fc polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 10 in FIG. 1 J. In some cases, amino acids 14 and 15 are both Ala, and the Ig Fc does comprise a Lys at the C -terminus.

[0122] In some cases, each TMP of a DTMP is a heterodimer comprising: a) a first polypeptide comprising: i) an HPV16 peptide having the amino acid sequence YMLDLQPETT (SEQ ID NO:20); ii) a peptide linker having the amino acid sequence (GGGGS)n (SEQ ID NO:64), where n is an integer from 1 to 10 (e.g., where n is 2, 3, or 4); iii) a P2M polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO:2 depicted in FIG. IB; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) a first variant IL -2 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO:22 depicted in FIG. 1U; ii) a peptide linker having the amino acid sequence (GGGGS)n (SEQ ID NO: 64), where n is an integer from 1 to 10 (e.g., where n is 2, 3, or 4); iii) a second variant IL-2 polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO:22 depicted in FIG. 1U; iv) a peptide linker having the amino acid sequence (GGGGS)n (SEQ ID NO: 64), where n is an integer from 1 to 10 (e.g., where n is 2, 3, or 4);Attorney Docket No. 33194-0001 WO v) an MHC class I heavy chain polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO:4 depicted in FIG. ID; vi) a peptide linker, e.g., a peptide comprising the amino acid sequence AAAGG (SEQ ID NO: 65); and v) an Ig Fc polypeptide comprising an amino acid sequence having at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to the following amino acid sequence of SEQ ID NO:9 depicted in FIG. II, wherein the Ig Fc optionally includes a Lys at the C terminus.

[0123] In some cases, each TMP of a DTMP is a heterodimer comprising: a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 19 depicted in FIG. IS; and b) a second polypeptide comprising, in order from N-terminus to C-terminus: i) a first variant IL -2 polypeptide comprising the amino acid sequence of SEQ ID NO:22 in FIG. 1U; ii) a peptide linker comprising the amino acid sequence (GGGGS)4 (SEQ ID NO:66); iii) a second variant IL-2 polypeptide comprising the amino acid sequence of SEQ ID NO:22 in FIG. 1U; iv) a peptide linker comprising the amino acid sequence (GGGGS)4 (SEQ ID NO:66); v) an MHC class I heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO 4 in FIG. ID; vi) a peptide linker comprising the amino acid sequence AAAGG (SEQ ID NO:65); and v) an Ig Fc polypeptide comprising the amino acid sequence of SEQ ID NO:9 in FIG.II.

[0124] In some cases, each TMP of a DTMP is a heterodimer comprising: a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 19 in FIG. I S); and b) a second polypeptide comprising the amino acid sequence SEQ ID NO: 17 depicted in FIG. IQ.Attorney Docket No. 33194-0001 WO

[0125] In some cases, each TMP of a DTMP is a heterodimer comprising: a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 19 in FIG. IS; and b) a second polypeptide comprising the amino acid sequence of SEQ ID NO: 18 depicted in FIG. 1R.

[0126] In any of the above exemplary TMPs, the HPV16 E7 peptide YMLDLQPETT (SEQ ID NO: 20) may be replaced by an HPVE6 peptide or a different HPV E7 peptide, including an HPV16 E6 or HPV16 E7 peptide.

[0127] In all of the above exemplary DTMPs of this section, the TMPs may be identical, in which case the DTMP will be a homodimer.FORMULATIONS, DOSAGES, AND ADMINISTRATION / CO- ADMINISTRATION OF THE DTMP

[0128] HPV+ cancers that can be treated with a method of this disclosure include cancers associated with HPV16 infections. Cancers that can be treated with a method include, e.g., newly diagnosed or recurrent and / or metastatic: HPV16+ head and neck cancers such as squamous cell carcinoma, oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer; anal cancer; penile cancer; vulvar cancer; vaginal cancer; and cervical cancer.

[0129] A composition can comprise, in addition to a fixed dose of a DTMP, one or more pharmaceutically acceptable carriers (substances used to transport active pharmaceutical ingredients (APIs) to their target sites in the body) and / or additives (inactive substances formulated alongside the API; also known as excipients). Such carriers and additives are well known in the art and need not be discussed in detail herein. See, for example, the ninth (or latest) edition of Sheskey et al., “Handbook of Pharmaceutical Excipients” (2020), and / or the 23rd(or latest) edition of “Remington: The Science and Practice of Pharmacy”, 23rd Ed. (2020).

[0130] Where a fixed dose of a DTMP is administered as an injectable (e.g. subcutaneously, intraperitoneally, intramuscularly, and / or intravenously) directly into a tissue, a formulation can be provided as a ready-to-use dosage form that may be directly injected or infused into the patient or admixed with a saline solution for infusion, or possibly as a non-aqueous form (e.g., a reconstitutable storage-stable powder). Formulations may also be provided so as to enhance serum half-life of the DTMP following administration. For example, the DTMP may be provided in a liposome formulation, prepared as a colloid, or other conventional techniques for extending serum half-life. The preparations may also be provided in controlled release or slow-release forms.Attorney Docket No. 33194-0001 WO

[0131] The concentration of a fixed dose of a DTMP in a liquid composition formulation can vary, and may depend on numerous factors, including the stability of the DTMP in the liquid composition.

[0132] In some cases, a fixed dose of a DTMP is present in a liquid composition. In some cases, a composition comprises: a) a fixed dose of a DTMP; and b) saline (e.g., 0.9% NaCl). In some cases, a fixed dose of a DTMP is intended to be mixed with saline (e.g., 0.9% NaCl). The composition typically will be sterile and suitable for administration to a human subject.

[0133] As discussed above, it has been discovered that a cancer patient in need of such treatment may be administered a fixed dose of a DTMP irrespective of the patient’s weight. That is, the dose administered to the patient is not dependent on, or adjusted for, the weight of the patient. Such fixed doses are therefore not based on the weight of any one individual patient. Fixed doses may fall within a range from about 150 mg to about 300 mg, e.g., from 135 mg to 330 mg, including the ranges of from 150 to 300 mg, from 135 mg to 165mg, from 165 mg to 270 mg, and from 270 mg to 330 mg. In some cases, a fixed dose of CUE-101 or other DTMP can be higher, e.g., from about 300 mg to about 450 mg, i.e., from 270 mg to 495 mg, including from 300 mg to 350 mg, from 350 mg to 400 mg, from 400 to 450 mg and 450 mg to 495 mg. In some cases, the fixed dose of CUE- 101 or DTMP can be lower than 150 mg, e g., from about 25 mg to about 50 mg, from about 50 mg to about 75 mg, from about 75 mg to about 100 mg, from about 100 mg to about 125 mg, and from about 125 mg to about 150 mg, including from 25 mg to 50 mg, from 50 mg to 75 mg, from 75 mg to 100 mg, from 100 mg to 125 mg, and from 125 mg to 150 mg. Included within the foregoing ranges are doses of about 25 mg, 25 mg, about 50 mg, 50 mg, about 100 mg, 100 mg, about 125 mg and 125mg.

[0134] Fixed doses of CUE-101 or other DTMP thus can include doses of about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg. Fixed doses of a DTMP such as CUE-101 can include doses of 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, and 330 mg. Included within such fixed doses are 150 mg, 225 mg and 300 mg, which are expected to provide a Cmax and AUC that are approximately equivalent to weight-based dosages of 2 mg / kg, 3 mg / kg and 4 mg / kg. In some cases, the amount of CUE-101 or other DTMP can be higher, e.g., from 330 mg to about 450 mg,Attorney Docket No. 33194-0001 WO including about 350 mg, 350 mg, about 375 mg, 375 mg, about 400 mg, 400 mg, about 425 mg, 425 mg, about 450 mg, 450 mg, which higher fixed doses are expected to provide a Cmax and AUC that are approximately equivalent to weight-based dosages of up to about 6 mg / kg. In some cases, the fixed dose of CUE-101 or other DTMP can be lower, e.g., from 25 mg to 50 mg, from 50 mg to 75 mg, from 75 mg to 100 mg, from 100 mg to 125 mg, and from 125 mg to 150 mg, which lower fixed doses are expected to provide a Cmax and AUC that are approximately equivalent to weight-based dosages lower than 2 mg / kg, e.g., from 0.33 mg / kg to 2 mg / kg. Accordingly, provided herein is a sealed container (e.g., a vial), or a plurality of sealed containers, each containing a ready-to-use pharmaceutical composition comprising one of the foregoing fixed dosages of a DTMP. Alternatively, a fixed dose may be divided among a plurality of sealed containers (e.g., vials), each containing a ready-to-use pharmaceutical composition comprising a predetermined portion of the fixed dose such that the contents of the plurality of sealed containers (e.g., vials) may be combined to provide the desired fixed dose of DTMP. For example, if a fixed dose of the DTMP such as CUE- 101 is 150 mg, then the fixed dose could be provided in a single vial of 150 mg or in two vials, each comprising 75 mg of the DTMP. If a fixed dose of DTMP such as CUE-101 is 300 mg, then the fixed dose could be provided in one vial of 300 mg, two vials of 150 mg each, three vials of 100 mg each, or four vials of 75 mg each. If a fixed dose of DTMP such as CUE-101 is 100 mg, then the fixed dose could be provided in one vial of 100 mg or two vials of 50 mg each. If a fixed dose of DTMP such as CUE-101 is 75 mg, then the fixed dose could be provided in one vial of 75 mg, two vials of 37.5 mg each, three vials of 25 mg each, or one vial of 50 mg and one vial of 25 mg. If a fixed dose of DTMP such as CUE-101 is 50 mg or 25 mg, then the fixed dose could be provided in one vial of 50 mg or 25 mg. The term “ready-to-use” thus means that the pharmaceutical composition, comprising an amount of DTMP in specified fixed dose, is ready to be removed from the sealed container, or from a plurality of containers if only a pre-determined portion of the fixed dose is provided in each of the plurality of containers, and then administered to a patient or prepared for administration to a patient (e.g., by mixing with saline or other diluent) without adjustment of the amount of the pharmaceutical composition to be administered based on the patient’s weight.Attorney Docket No. 33194-0001 WO

[0135] Where the fixed dose of DTMP such as CUE-101 is provided as a formulation suitable for subcutaneous administration, the fixed dose of DTMP may be provided as a pre-filled syringe, or alternatively as a plurality of pre-filled syringes that each contain a predetermined portion of the fixed dose. Accordingly, this disclosure provides a package comprising one or a plurality of such pre-filled syringes containing either a fixed dose or a predetermined portion of a fixed dose.

[0136] Also provided is a kit or a plurality of kits for treating a patient with a fixed dose of CUE- 101 or other DTMP according to this disclosure. Such kits can comprise one or more sealed containers (e.g. vials), each sealed container containing a ready-to-use pharmaceutical composition comprising a fixed dose of a DTMP such as CUE-101, together with instructions for administering the pharmaceutical composition comprising the fixed dose of CUE-101 or other DTMP (optionally including instructions for diluting the pharmaceutical composition comprising a fixed dose, if allowed). The instructions can direct the administration for any one of the methods described herein, including but not limited to methods of treating an HPV-associated cancer, and / or methods in which the fixed dose of DTMP is co-administered with another active agent. For example, the instructions can direct the administration of the fixed dose of DTMP with a cellular therapy composition (e.g., CAR-T cells or TCR-T cells) that comprise a target TCR to which the pMHC of CUE-101 or at least one TMP of another DTMP specifically binds. As another example, the instructions can direct the administration of the fixed dose of DTMP with a checkpoint inhibitor (CPI) as described below. As another example, the instructions can direct the administration of the fixed dose of DTMP with a protein described below that comprises CPI functionality such as a multi-specific antibody (e.g., a bispecific antibody) or muti-target fusion protein that binds to one or more immune checkpoints, and also may bind to a protein other than an immune checkpoint.

[0137] As noted above, a fixed dose of DTMP such as CUE-101 may be divided among a plurality of sealed containers (e.g., vials), each containing a pre-determined portion of the fixed dose of a DTMP. In such a case, the kit would contain multiple sealed containers (e.g., vials) of a ready-to- use pharmaceutical composition each comprising a pre-determined portion of the fixed dose of DTMP, such that the contents of the plurality of containers (e.g., vials) would be combined to provide the desired fixed dose. For example, if a fixed dose of the DTMP such as CUE-101 is 100 mg, then a kit might contain two vials, each comprising 50 mg of the DTMP. If a fixed dose of the DTMP such as CUE-101 is 150 mg, then a kit might contain two vials, each comprising 75 mg of the DTMP, or one vial containing 100 mg and another vial containing 50 mg. If a fixed dose ofAttorney Docket No. 33194-0001 WODTMP such as CUE-101 is 300 mg, then the kit might contain four vials, each comprising 75 mg of the DTMP, or two vials, each comprising 150 mg, and so on. Such a kit also may include an extra vial in case there is a problem with one of the vials in the kit.

[0138] In some cases, therefore, such a kit or kits may be used for treating an individual suffering from an HPV+ cancer, including an HPV16+ cancer such as an oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer, penile cancer, anal cancer, vaginal cancer, vulvar cancer, or cervical cancer. In such cases, the kit comprising one or more sealed containers (e.g. vials), each sealed container containing a ready-to-use pharmaceutical composition comprising a fixed dose of a DTMP such as CUE-101, together with instructions for using the pharmaceutical composition (optionally including instructions for diluting the pharmaceutical composition comprising a fixed dose, if allowed) can be used in a method of treating the cancer of a patient in need of such treatment. Alternatively, as noted above, a fixed dose of DTMP may be divided among a plurality of sealed containers (e.g., vials), each containing a ready- to-use pharmaceutical composition comprising a pre-determined portion of the fixed dose. As described above, in such a case, the kit would contain multiple sealed containers (e.g., vials) of a ready-to-use pharmaceutical composition each comprising a pre-determined portion of the fixed dose of DTMP, such that the contents of the plurality of containers (e.g., vials) would be combined to provide the desired fixed dose. For example, if a fixed dose of the DTMP such as CUE-101 is 150 mg, then a kit might contain two vials, each comprising 75 mg of the DTMP. If a fixed dose of DTMP such as CUE-101 is 300 mg, then the kit might contain four vials, each comprising 75 mg of the DTMP, or two vials, each comprising 150 mg. Such a kit also may include an extra vial in case a problem is encountered with one of the vials in the kit.

[0139] Those of skill will readily appreciate that dose levels can vary as a function of the specific homodimeric DTMP, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determined by qualified medical professionals by a variety of means. The frequency of administration can vary depending on any of a variety of factors, e.g., severity of unwanted side effects, etc. For example, in some cases, a fixed dose of a DTMP is administered once every three weeks as in the CUE-101-01 clinical trial. Alternatively, as determined by an appropriate medical professional, the DTMP can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), once every two weeks, or once every four weeks, once every five weeks, once every six weeks,Attorney Docket No. 33194-0001 WO once every two months, or less frequently. Once every three weeks may be commonly employed at the beginning of treatment, but other frequencies are possible, for example if the DTMP is being coadministered with another drug that has a different dosing frequency.

[0140] The duration of administration of a fixed dose of a DTMP such as CUE-101, either alone or in combination with another active agent such as a CPI (discussed below), will be determined by a qualified medical professional, and can depend on a variety of factors. For example, a fixed dose of a DTMP can be administered in combination with a CPI over a period of time ranging from weeks to months and continued until the patient is determined to have progressive disease under RECIST criteria, e.g., RECIST 1.1, iRECIST, or irRECIST. If administered in a neo-adjuvant setting, the length of time may be from only one to a few weeks and the DTMP may be administered only once or only a few times, e.g., two, three or four times, before a main treatment such as surgery. In an adjuvant setting following initial treatment such as chemotherapy and / or radiation, or a setting in which the patient is being treated for a cancer that has newly appeared or is recurrent or metastatic, the treatment duration may continue indefinitely or until the patient exhibits progressive disease as determined by RECIST criteria such as RECIST 1.1, iRECIST, or irRECIST.Co-administration of fixed doses of DTMPs with other drugs

[0141] Fixed doses of DTMPs of this disclosure such as CUE-101 may be administered in combination with other with other drugs such as immune checkpoint inhibitors, agents that bind HPV E5 protein, cellular therapy agents such as CAR-T cells and TCR-T cells, and chemotherapeutic agents. Such co-administration may be at the same time or on the same schedule, or may be at different times and / or on a different schedule.Fixed Doses of a DTMP with Immune Checkpoint Inhibitors (CPIs)

[0142] Immune checkpoint inhibitors (CPIs) are well known immuno-oncology drugs that can make a patient’s cancer more susceptible to being killed by the patient’s own cancer-specific T cells. Because DTMPs can increase the number of cancer-specific T cells in a patient, they can have a complimentary mechanism of action with CPIs and achieve a therapeutic benefit that is greater than either alone. Such an enhanced effect has already been shown to date in Parts C and D of the CUE- 101-01 trial discussed below in Example 1, in which CUE-101 is administered in combination with the anti-PDl CPI pembrolizumab (Keytruda®).Attorney Docket No. 33194-0001 WO

[0143] Co-administration of a fixed dose of a DTMP and CPI means that both are administered to an individual, although not necessarily at the same time, in order to achieve a therapeutic effect that is the result of having administered both the fixed dose of a DTMP and the CPI. The schedule of administering the DTMP and CPI can be determined by a qualified medical professional. For example, each of CUE-101 and the CPIs pembrolizumab and cemiplimab may be administered once every three weeks. Hence, CUE-101 possibly can be administered with either CPI during the same patient visit.

[0144] Exemplary CPIs include inhibitors (typically antibodies) that target an immune checkpoint polypeptide such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, CD122, PD-1, PD- L1 and PD-L2. Commonly administered CPIs include anti-PDl antibodies such as nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®), dostarlimab (Jemperli®), retifanlimab (Zynyx®), toripalimab (Loqtorz®), and tislelizumab (Tevimbra®), anti-PD-Ll antibodies such as durvalumab (imfinzi®), atezolizumab (tecentriq®), and avelumab (Bavencio®), anti-CTLA-4 antibodies such as ipilimumab (Yervoy®) and tremelimumab (Imjudo®), and also antibodies that bind TIGIT or LAG3.

[0145] Among CPIs, the CPIs that interfere with the binding of PD-1 to PD-L1 have become an important weapon in the fight against cancers that express the checkpoint PD-L1. Such CPIs, which commonly are antibodies that bind either to PD-1 on cytotoxic T cells (CTLs), or bind to PD-L1 on cancer cells, are collectively denoted as “PD-(L)1 CPIs.” By blocking the binding of PD-1 on a CTL to PD-L1 on a cancer cell, these antibodies prevent deactivation of CTLs, which allows the CTLs to release their cytotoxins and kill the cancer cell. In this way, CPIs actually help a patient’s own immune system to detect and eliminate cancer cells.

[0146] One of the most commonly administered PD-(L)1 CPIs is pembrolizumab (Keytruda®), which is typically administered in an amount of 200 mg every three weeks or 400 mg every six weeks. Hence, a fixed dose of a DTMP such as CUE-101 (e.g., a 150 mg dose or 300 mg dose), can be administered every three weeks with 200 mg of pembrolizumab, every six weeks with 400 mg of pembrolizumab, or every three weeks, with 400 mg of pembrolizumab being administered every six weeks. Pembrolizumab is normally administered intravenously, but also may be provided in a formulation suitable for subcutaneous injection. Hence, a DTMP such as CUE-101, which alsoAttorney Docket No. 33194-0001 WO may be formulated for subcutaneous injection, and pembrolizumab, may each be provided in a form for subcutaneous injection, e.g., as separate pre-fdled syringes, for administration by a medical professional or for self-administration by a patient.

[0147] Another of the most commonly administered PD-(L)1 CPIs is nivolumab (Opdivo" ), which is typically administered in an amount of 240 mg every 2 weeks or 480 mg every 4 weeks. Hence, a fixed dose of a DTMP such as CUE-101 (e.g., a 150 mg dose or 300 mg dose), can be administered every two weeks with 240 mg of nivolumab, or every four weeks with 480 mg of nivolumab. Alternatively, a fixed dose of a DTMP such as CUE-101 (e.g., a 150 mg dose or 300 mg dose), can be administered every three weeks, with 240 mg of nivolumab being administered every two weeks or 480 mg of nivolumab being administered every four weeks. Nivolumab is normally administered intravenously, but also may be provided in a formulation suitable for subcutaneous injection. Hence, a DTMP such as CUE-101, which also may be formulated for subcutaneous injection, and nivolumab, may each be provided in a form for subcutaneous injection, e.g., as separate pre-filled syringes, for administration by a medical professional or for selfadministration by a patient.

[0148] Another commonly administered PD-(L)1 CPIs is cemiplimab (Libtayo®), which is typically administered in an amount of 350 mg every three weeks. Hence, a fixed dose of a DTMP such as CUE-101 (e.g., a 150 mg dose or 300 mg dose), can be administered every three weeks with 350 mg of cemiplimab. If cemiplimab is provided in a formulation suitable for subcutaneous injection, then cemiplimab and a DTMP such as CUE- 101 may each be provided in a form for subcutaneous injection, e.g., as separate pre-filled syringes, for administration by a medical professional or for self-administration by a patient.

[0149] The duration of administration of a combination of a fixed dose of a DTMP and a CPI can vary, depending on any of a variety of factors, and will be determined by a qualified medical professional. For example, a fixed dose of a DTMP can be administered in combination with a CPI over a period of time ranging from weeks to months and continued until the patient is determined to have progressive disease under RECIST criteria, e.g., RECIST 1.1, iRECIST, or irRECIST. The length of time may depend on whether the DTMP and CPI are administered in a neoadjuvant setting, in which case they may be administered only once or only a few times, e.g., two, three or four times, for only a week or a few weeks before a main treatment such as surgery. In an adjuvant setting following initial treatment such as chemotherapy and / or radiation, or a setting in which the patientAttorney Docket No. 33194-0001 WO is being treated for a cancer that has newly appeared or is recurrent or metastatic, the treatment with both the DTMP and CPI may continue indefinitely or until the patient exhibits progressive disease as determined by RECIST criteria such as RECIST 1.1, iRECIST, or irRECIST.

[0150] When administering a PD-(L)1 CPI, a patient may first be evaluated to determine the patient’s Combined Positive Score or CPS, which is a metric used in cancer immunotherapy to evaluate the expression of the PD-L1 checkpoint protein in tumor tissues. A fixed dose of a DTMP such as CUE-101 can be administered in combination with a PD-(L)1 CPI to a patient who has a CPS of 0, from 0-1 or from 1-19 (a low CPS patient), or from 20 to 100 (a high CPS patient).

[0151] Accordingly, patients who were previously treated with a PD-(L)1 CPI such as pembrolizumab, nivolumab, cemiplimab, or durvalumab, either alone or in combination with one or more therapeutic agents (e.g., one or more chemotherapeutic agents), and were determined to have progressive disease based on RECIST 1.1 criteria, may benefit from receiving a combination treatment of an effective amount of a fixed dose of a DTMP of this disclosure, e g., CUE-101, in combination with a PD-(L)1 CPI such as pembrolizumab, nivolumab, cemiplimab, or durvalumab. Such patients can include patients who have a PD-L1 CPS of 0 or more than 0 to less than 1, from 1 to 19, or from 20 to 100, whether newly diagnosed, or having been previously diagnosed with cancer, may also benefit from receiving the combination of a fixed dose of a DTMP and PD-(L)1 CPI. Such patients may include individuals who (i) had no prior therapies following an initial diagnosis of HPV16+ cancer, (ii) had at least one prior therapy following an initial diagnosis of HPV16+ cancer and have been determined to have progressive disease, (iii) are receiving the combination as a neoadjuvant therapy for an HPV16+ cancer, (iv) are receiving the combination as an adjuvant therapy for an HPV16+ cancer, (v) are receiving the combination as a first line treatment following a diagnosis of recurrent and / or metastatic HPV16+ cancer, or (vi) are receiving the combination as a second line or beyond therapy following a diagnosis of recurrent and / or metastatic HPV16+ cancer and treatment with a prior therapy following the diagnosis of recurrent and / or metastatic HPV16+ cancer and have been diagnosed with progressive disease following such prior treatment. Such patients also may include individuals who, due to having a PD-L1 CPS below 1, might not qualify for treatment with some PD-(L)1 CPIs such as pembrolizumab (either alone or in combination with one or more therapeutic agents such as chemotherapeutic agents).Fixed Doses of a DTMP with Proteins Comprising CPI FunctionalityAttorney Docket No. 33194-0001 WO

[0152] Multi-specific antibodies (e.g., bispecific antibodies) and multi-target fusion proteins comprising CPI functionality are of increasing interest in the treatment of cancer. Such antibodies and fusion proteins bind to one or more immune checkpoints such as PD-1, PD-L1, CTLA-4, TIGIT, PVRIG and / or CD96. Many such antibodies and fusion proteins additionally bind to a non-CPI target such as VEGF, 4-1BB, or TGF-p, with VEGF being a common target (including members of the VEGF family of angiogenic proteins such as VEGF-A, or VEGF receptors such as VEGFR1).

[0153] Such multi-specific (e.g., bi specific) antibodies and fusion proteins include, but are not limited to BNT327, which binds to both PD-L1 and VEGF), PM1009, which binds to both TIGIT and PVRIG, PM 1022, which binds to both PD-L1 and TIGIT, PM8001, which binds to both PD-L1 and TGF-P, PM1003, which binds to PD-L1 and 4-1BB, LM-299, which binds to both PD-1 and VEGF, Ivonescimab, which binds to both PD-1 and VEGF, SSGJ-707, which binds both VEGF and PD-1, AP505, which binds to both PD-1 and VEGF, JS207, which binds to both PD-1 and VEGF- A, Palverafusp alfa, which binds to both PD-1 and VEGF, RC148, which binds to both PD-1 and VEGF, Sotiburafusp alfa, which binds to VEGFR1 and PD-L1, AI-081, which binds to both PD-1 and VEGF, MHB039A, which binds to both PD-1 and VEGF, MK-2010, which binds to both PD-1 and VEGF, CVL006, which binds to both PD-L1 and VEGF, and SGI408, which binds to both PD- L1 and VEGF.

[0154] As discussed above, because DTMPs can increase the number of cancer-specific T cells in a patient, they can have a complimentary mechanism of action with such multi-specific (e.g., bispecific) antibodies and fusion proteins, and can achieve a therapeutic benefit that is greater than either alone.

[0155] Co-admini strati on of a fixed dose of a DTMP and such multi-specific (e g., bispecific) antibodies or multi-specific (e.g., bispecific) fusion proteins means that both are administered to an individual, although not necessarily at the same time, in order to achieve a therapeutic effect that is the result of having administered both the fixed dose of a DTMP and the multi-specific (e.g., bispecific) antibody or multi-specific fusion protein. The schedule of administering the DTMP and multi-specific (e.g., bispecific) antibody or multi-specific fusion protein can be determined by a qualified medical professional.Other active agentsAttorney Docket No. 33194-0001 WO

[0156] Fixed doses of DTMPs such as CUE-101 may be co-administered with other drugs that have activity against HPV+ cancers such as HPV16+ cancers. One such group of drugs directly binds the HPV16 E5 protein, which is a protein that can help the virus evade the immune system. Such drugs include TGN-S11 and TGN-S15 (Toragen), or derivatives of TGN-S11 or TGN-S15.

[0157] Fixed doses of DTMPs such as CUE-101 also may be co-administered with cellular therapy products such as CAR-T cells that are designed to bind to and kill cells that express an HPV antigen such as HPV E6 or HPV E7 (e g., HPV16 E6 or HPV16 E7). Fixed doses of DTMPs such as CUE- 101 also may be co-administered with CAR-T cells that comprise a chimeric antigen receptor (i.e., a “CAR”) that binds to antigens on cancer cells other than HPV-expressing cancer cells. See e.g., published PCT applications WO 2021 / 081232 and WO 2023 / 212551 to Cue Biopharma, Inc., the contents of which as they pertain to the administration of DTMPs, including but not limited to CUE- 101, to activate and proliferate CAR-T cells comprising a target TCR and a CAR that binds to an HPV or non-HPV antigen, are expressly incorporated herein by reference. In such cases, the CAR- T cells comprise an endogenous or exogenous TCR to which the pMHC of CUE-101 or other DTMP specifically binds, in which case the DTMP can bind to the TCR-T cell and provide stimulation so as to activate and / or proliferate the TCR-T cells. In this way, periodic dosing of the DTMP to a patient following administration of the CAR-T cells can prolong the persistence of the CAR-T cells in the patient. Similarly, fixed doses of DTMPs such as CUE-101 may be co-administered with TCR-T cells that comprise a TCR that binds to an antigen expressed on the surface of an HPV cancer cell such as an HPV 16 cancer cell. In such cases, the pMHC of the DTMP can be designed to bind to the TCR of the TCR-T cell and provide stimulation so as to activate and / or proliferate the TCR- T cell and thereby prolong the persistence of the TCR-T cells.EXAMPLES OF NON-LIMITING ASPECTS OF THE DISCLOSURE

[0158] Aspects, including embodiments, of the present subject matter described above may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such permutations and combinations of aspects and is not limited to combinations of aspects explicitly provided below.Attorney Docket No. 33194-0001 WOAspect Section A1. A sealed container containing a fixed dose of a dimeric T cell modulatory protein (DTMP), wherein the DTMP comprises two T cell modulatory proteins (TMPs), wherein each TMP comprises the following components: i) an HPV cancer-associated peptide (HPV peptide), optionally wherein the HPV peptide is a peptide having a length of from 8 amino acids to 14 amino acids; ii) a p2-microglobulin (02M) polypeptide; iii) one or more immunomodulatory polypeptides, wherein the one or more immunomodulatory proteins comprise a variant IL-2 polypeptide that exhibits reduced affinity to IL-2R; iv) a class I major histocompatibility complex (MHC) heavy chain polypeptide; and v) an immunoglobulin (Ig) Fc polypeptide, wherein each TMP may comprise one or more independently selected peptide linkers between any two of the component polypeptides, and wherein when each TMP comprises more than one immunomodulatory polypeptide, the immunomodulatory polypeptides may be connected by one or more independently selected peptide linkers, wherein the two TMPs are linked by one or more disulfide bonds that join the Ig Fc polypeptide of one TMP to the Ig Fc polypeptide of the other TMP, wherein each TMP comprises a peptide-MHC complex (pMHC) that can specifically bind to a T-cell receptor (TCR) of a T cell, wherein the fixed dose of the DTMP is not based on the weight of a patient, and wherein the fixed dose of the DTMP is from about 25 mg to about 135 mg, from about 50 mg to about 125 mg, from about 75 mg to about 100 mg, from about 135 mg to about 330 mg, from about 150 to about 300 mg, from about 135 mg to about 165 mg, from about 165 mg to about 270 mg, from about 270 mg to about 330 mg, from about 350 to about 400 mg, from about 450 mg to about 495 mg, from 25 mg to 135 mg, from 50 mg to 125 mg, from 75 mg to 100 mg, from 135 mg to 330 mg, from 150 to 300 mg, from 135 mg to 165 mg, from 165 mg to 270 mg, or from 270 mg to 330 mg, from 350 to 400 mg, or from 450 mg to 495 mg.Attorney Docket No. 33194-0001 WO2. A plurality of sealed containers, each comprising a predetermined portion of a fixed dose of a dimeric T cell modulatory protein (DTMP), wherein the DTMP comprises two T cell modulatory proteins (TMPs), wherein each TMP comprises the following components: i) an HPV peptide, optionally wherein the HPV peptide is a peptide having a length of from 8 amino acids to 14 amino acids; ii) a p2-microglobulin (P2M) polypeptide; iii) one or more immunomodulatory polypeptides, wherein the one or more immunomodulatory proteins comprise a variant IL-2 polypeptide that exhibits reduced affinity to IL-2R; iv) a class I major histocompatibility complex (MHC) heavy chain polypeptide; and v) an immunoglobulin (Ig) Fc polypeptide, wherein each TMP may comprise one or more independently selected peptide linkers between any two of the components, and wherein when the TMP comprises more than one immunomodulatory polypeptide, the immunomodulatory polypeptides may be connected by one or more independently selected peptide linkers, wherein the TMPs are linked by one or more disulfide bonds that join the Ig Fc polypeptide of one TMP to the Ig Fc polypeptide of the other TMP, wherein each TMP comprises a peptide-MHC complex (pMHC) that can specifically bind to a T-cell receptor (TCR) of a T cell, wherein the fixed dose of the DTMP is not determined based on the weight of any one individual patient, and wherein the fixed dose of the DTMP is from about 25 mg to about 135 mg, from about 50 mg to about 125 mg, from about 75 mg to about 100 mg, from about 135 mg to about 330 mg, from about 150 to about 300 mg, from about 135 mg to about 165 mg, from about 165 mg to about 270 mg, from about 270 mg to about 330 mg, from about 350 to about 400 mg, from about 450 mg to about 495 mg, from 25 mg to 135 mg, from 50 mg to 125 mg, from 75 mg to 100 mg, from 135 mg to 330 mg, from 150 to 300 mg, from 135 mg to 165 mg, from 165 mg to 270 mg, or from 270 mg to 330 mg, from 350 to 400 mg, or from 450 mg to 495 mg.3. A sealed container or plurality of sealed containers comprising means for treating an HPV-positive cancer in a patient in need thereof, wherein the means is a fixed dose of a dimericAttorney Docket No. 33194-0001 WOT cell modulatory protein (DTMP), wherein the DTMP comprises two T cell modulatory proteins (TMPs), wherein each TMP comprises the following components: i) an HPV cancer-associated peptide (HPV peptide), optionally wherein the HPV peptide is a peptide having a length of from 8 amino acids to 14 amino acids; ii) a 2-microglobulin (P2M) polypeptide; iii) one or more immunomodulatory polypeptides, wherein the one or more immunomodulatory proteins comprise a variant IL -2 polypeptide that exhibits reduced affinity to IL-2R; iv) a class I major histocompatibility complex (MHC) heavy chain polypeptide; and v) an immunoglobulin (Ig) Fc polypeptide, wherein each TMP may comprise one or more independently selected peptide linkers between any two of the component polypeptides, and wherein when each TMP comprises more than one immunomodulatory polypeptide, the immunomodulatory polypeptides may be connected by one or more independently selected peptide linkers, wherein the two TMPs are linked by one or more disulfide bonds that join the Ig Fc polypeptide of one TMP to the Ig Fc polypeptide of the other TMP, wherein each TMP comprises a peptide-MHC complex (pMHC) that can specifically bind to a T-cell receptor (TCR) of a T cell, wherein the fixed dose of the DTMP is not based on the weight of a patient, and wherein the fixed dose of the DTMP is from about 25 mg to about 135 mg, from about 50 mg to about 125 mg, from about 75 mg to about 100 mg, from about 135 mg to about 330 mg, from about 150 to about 300 mg, from about 135 mg to about 165 mg, from about 165 mg to about 270 mg, from about 270 mg to about 330 mg, from about 350 to about 400 mg, from about 450 mg to about 495 mg, from 25 mg to 135 mg, from 50 mg to 125 mg, from 75 mg to 100 mg. from 135 mg to 330 mg, from 150 to 300 mg, from 135 mg to 165 mg, from 165 mg to 270 mg, or from 270 mg to 330 mg, from 350 to 400 mg, or from 450 mg to 495 mg.4. The sealed container or plurality of sealed containers or means of aspects 1, 2 or 3, wherein each TMP is a heterodimer that comprises: a) a first polypeptide comprising: i) the HPV peptide; and ii) the p2-microglobulin (P2M) polypeptide; and b) a second polypeptide comprising:Attorney Docket No. 33194-0001 WO i) the one or more immunomodulatory polypeptides; ii) the MHC class I heavy chain polypeptide; and iii) an immunoglobulin (Ig) Fc polypeptide, or wherein: al) the first polypeptide comprises, in order from N-terminus to C-terminus: i) the HPV peptide; ii) a peptide linker; and iii) the P2M polypeptide; and bl) the second polypeptide comprises, in order from N-terminus to C-terminus: i) the one or more immunomodulatory polypeptides; ii) an optional linker; iii) the MHC class I heavy chain polypeptide; iv) an optional linker; and v) the Ig Fc polypeptide, or a2) the first polypeptide comprises, in order from N-terminus to C-terminus: i) the HPV peptide; ii) a peptide linker; and iii) the P2M polypeptide; and b2) the second polypeptide comprises, in order from N-terminus to C-terminus: i) the MHC class I heavy chain polypeptide; ii) an optional linker; iii) the Ig Fc polypeptide; iv) an optional linker; and v) the one or more immunomodulatory polypeptides, wherein when each TMP comprises more than one immunomodulatory polypeptide, the TMP may comprise one or more linkers between the immunomodulatory polypeptides, and optionally wherein at least one TMP of the DTMP further comprises a targeting polypeptide that binds to an antigen on an HPV 16-positive cancer cell.5. The sealed container or plurality of sealed containers or means of aspect 4, wherein the heterodimer comprises a disulfide bond formed between a Cys residue in the P2M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide.Attorney Docket No. 33194-0001 WO6. The sealed container or plurality of sealed containers or means of any one of aspects 4 or 5, wherein the heterodimer comprises a disulfide bond formed between (i) a Cys residue in a Cys-containing linker interposed between the HPV peptide and the P2M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide.7. The sealed container or plurality of sealed containers or means of aspect 5 or 6, wherein the first polypeptide and the second polypeptide are covalently linked to one another by at least a first and second disulfide bond, wherein the first disulfide bond is formed between (i) a Cys residue in a Cys-containing linker between the HPV peptide and the P2M polypeptide, and (ii) a Cys residue in the MHC class1 heavy chain polypeptide; and wherein the second disulfide bond is formed between a Cys residue in the P2M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide.8. The sealed container or plurality of sealed containers or means of any one of aspects 1-7, wherein at least one of the one or more immunomodulatory polypeptides comprise a variant IL-2 immunomodulatory polypeptide that exhibits decreased or substantially no binding to IL-2Ra, and also decreased binding to IL-2Rp.9. The sealed container or plurality of sealed containers or means of aspect 8, wherein the amino acid sequence of the variant IL-2 polypeptide has a percent sequence identity that is at least 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence set forth in SEQ ID NO:21.10. The sealed container or plurality of sealed containers or means of aspect 9, wherein amino acid 16 is other than histidine and amino acid 42 is other than phenylalanine.11. The sealed container or plurality of sealed containers or means of any one of aspects 9 or 10, wherein amino acid 16 is Ala, Thr, Asp or Glu, and wherein amino acid 42 is Ala, optionally wherein amino acid 16 is Ala and amino acid 42 is Ala.12. The sealed container or plurality of sealed containers or means of any one of aspects 1-11, wherein each TMP comprises two variant IL-2 polypeptides.13. The sealed container or plurality of sealed containers or means of any one of aspects 1-12, wherein each TMP comprises two variant IL-2 polypeptides in tandem, and wherein the twoAttorney Docket No. 33194-0001 WO variant IL-2 polypeptides have the same amino acid sequence and optionally are connected by a linker.14. The sealed container or plurality of sealed containers or means of any one of aspects 4-13, wherein each TMP comprises a variant Ig Fc polypeptide comprising one or more amino acid substitutions that reduce or substantially eliminate antibody-dependent cell-mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC).15. The sealed container or plurality of sealed containers or means of any one of aspects 4-14, wherein each TMP comprises a variant Ig Fc polypeptide comprising an amino acid sequence having at least about 95% amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:7-10 (FIG. 1G-1J), optionally wherein each TMP comprises a variant Ig Fc polypeptide comprising an amino acid sequence having at least about 98% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NOTO, and comprises an Ala at amino acid 14 and an Ala at amino acid 15, based on the amino acid numbering depicted in SEQ ID NO:9.16. The sealed container or plurality of sealed containers or means of any one of aspects 9-15, wherein each TMP comprises two variant IL-2 polypeptides in tandem, and wherein the two variant IL-2 polypeptides are optionally connected by a linker.17. The sealed container or plurality of sealed containers or means of aspect 16, wherein a) the first polypeptide of each heterodimer comprises, in order from N-terminus to C-terminus: i) the HPV peptide , wherein the peptide has a length of 8-12 amino acids; ii) a peptide linker; and iii) the P2M polypeptide, wherein the P2M polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NOT or SEQ ID NO:2; b) the second polypeptide of each heterodimer comprises, in order from N-terminus to C-terminus: i) the first variant IL-2 polypeptide; ii) a second variant IL-2 polypeptide;Attorney Docket No. 33194-0001 WO iii) the MHC class I heavy chain polypeptide, wherein the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:3; and iv) the Ig Fc polypeptide, wherein each variant IL-2 polypeptide has at least 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:21, wherein amino acid 16 is other than histidine and amino acid 42 is other than phenylalanine, and wherein the second polypeptide comprises an independently selected peptide linker between one or more of: a) the first immunomodulatory polypeptide and the second immunomodulatory polypeptide; b) the second immunomodulatory polypeptide and the MHC class I heavy chain polypeptide; and c) the MHC class I heavy chain polypeptide and the Ig Fc polypeptide.18. The sealed container or plurality of sealed containers or means of aspect 17, wherein a) the first polypeptide of each heterodimer comprises, in order from N-terminus to C-terminus: i) the HPV peptide, wherein the peptide has a length of 8-12 amino acids; ii) a peptide linker; and iii) the P2M polypeptide, wherein the 02M polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:2; b) the second polypeptide of each heterodimer comprises, in order from N-terminus to C-terminus: i) the MHC class I heavy chain polypeptide, wherein the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:3; ii) the Ig Fc polypeptide; iii) the first variant IL-2 polypeptide; and iv) a second variant IL-2 polypeptide, wherein each variant IL-2 polypeptide has at least 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:21, wherein amino acid 16 is other than histidine and amino acid 42 is other than phenylalanine, andAttorney Docket No. 33194-0001 WO wherein the second polypeptide comprises an independently selected peptide linker between one or more of: a) the MHC class I heavy chain polypeptide and the Ig Fc polypeptide b) the Ig Fc polypeptide the first immunomodulatory polypeptide; and c) the first immunomodulatory polypeptide and the second immunomodulatory polypeptide.19. The sealed container or plurality of sealed containers or means of aspect 17 or 18, wherein: i) the P2M polypeptide comprises a Cys at amino acid 12 based on the amino acid numbering of SEQ ID NO:2; and ii) the class I MHC polypeptide comprises a Cys at residue 236 based on the amino acid numbering of SEQ ID NO: 4, wherein each heterodimer comprises a disulfide bond linking the first polypeptide to the second polypeptide, and wherein the disulfide bond joins the Cys at amino acid 12 of the P2M polypeptide to the Cys at amino acid 236 of the MHC heavy chain polypeptide, and wherein the Ig Fc polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NOTO.20. The sealed container or plurality of sealed containers or means of aspect 19, wherein: i) the P2M polypeptide comprises the amino acid sequence set forth in SEQ ID NO:2; ii) the first and second variant IL-2 polypeptides comprise the amino acid sequence set forth in SEQ ID NO: 22; iii) the MHC class I heavy chain polypeptide comprises the amino acid sequence set forth in SEQ ID NO:4; and iv) the Ig Fc polypeptide comprises an amino acid sequence having at least about 98% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NOTO, and comprises an Ala at amino acid 14 and an Ala at amino acid 15 based on the amino acid numbering depicted in SEQ ID NO: 9, and wherein the second polypeptide comprises a peptide linker between: a) the first and second immunomodulatory polypeptides;Attorney Docket No. 33194-0001 WO b) the second variant immunomodulatory polypeptide and the MHC class I heavy chain polypeptide; and c) the MHC class I heavy chain polypeptide and the Ig Fc polypeptide.21. The sealed container or plurality of sealed containers or means of aspect 1 or 2, wherein each TMP comprises a single-chain polypeptide, and wherein the single-chain polypeptide comprises from N-terminus to C-terminus: i) the HPV peptide; ii) an optional peptide linker; iii) the P2M polypeptide; iv) an optional peptide linker; v) the MHC class I heavy chain polypeptide; vi) an optional peptide linker; vii) an immunoglobulin (Ig) Fc polypeptide; viii) an optional peptide linker; and ix) the one or more immunomodulatory polypeptides.22. The sealed container or plurality of sealed containers or means of aspect 21, wherein at least one of the one or more immunomodulatory polypeptides comprise a variant IL-2 immunomodulatory polypeptide that exhibits decreased or substantially no binding to IL-2Ra, and also decreased binding to IL-2Rp.23. The sealed container or plurality of sealed containers or means of aspect 22, wherein the amino acid sequence of the variant IL -2 polypeptide has a percent sequence identity that is at least 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence set forth in SEQ ID NO:21.24. The sealed container or plurality of sealed containers or means of aspect 23, wherein amino acid 16 is other than histidine and amino acid 42 is other than phenylalanine.25. The sealed container or plurality of sealed containers or means of aspect 23 or 24, wherein amino acid 16 is Ala, Thr, Asp or Glu, and wherein amino acid 42 is Ala, optionally wherein amino acid 16 is Ala and amino acid 42 is Ala.Attorney Docket No. 33194-0001 WO26. The sealed container or plurality of sealed containers or means of any one of aspects 21-25, wherein each TMP comprises two variant IL-2 polypeptides.27. The sealed container or plurality of sealed containers or means of any of aspects 21-26, wherein each TMP comprises two variant IL-2 polypeptides in tandem, and wherein the two variant IL-2 polypeptides have the same amino acid sequence and optionally are connected by a linker.28. The sealed container or plurality of sealed containers or means of any one of aspects 21-27, wherein the P2M polypeptide comprises an amino acid sequence having a percent sequence identity that is at least 95% of the amino acid sequence set forth in SEQ ID NO:21, wherein amino acid 16 is other than histidine and amino acid 42 is other than phenylalanine amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO:2, and wherein the MHC class I heavy chain polypeptide comprises an amino acid sequence having at least 95% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NOT.29. The sealed container or plurality of sealed containers or means of any one of aspects 21-28, wherein the Ig Fc polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:7-10, and wherein the Ig Fc polypeptide is a variant Ig Fc polypeptide comprising one or more amino acid substitutions that reduce or substantially eliminate antibody-dependent cell-mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC).30. The sealed container or plurality of sealed containers or means of aspect 29, wherein each TMP comprises a variant Ig Fc polypeptide comprising an amino acid sequence having at least about 95% amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:7-10 (FIG. 1G-1 J), optionally wherein each TMP comprises a variant Ig Fc polypeptide comprising an amino acid sequence having at least about 98% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NOTO, and comprises an Ala at amino acid 14 and an Ala at amino acid 15, based on the amino acid numbering depicted in SEQ ID NO:9.Attorney Docket No. 33194-0001 WO31. The sealed container or plurality of sealed containers or means of any one of aspects 21-30, wherein each TMP comprises a Cys-containing peptide linker between the cancer-associated peptide and the 02M polypeptide, and wherein each TMP comprises an intrachain disulfide bond between the Cys present in the peptide linker and a Cys in the MHC class I heavy chain polypeptide.32. The sealed container or plurality of sealed containers or means of aspect 31, wherein the MHC class I heavy chain polypeptide comprises a Cys at any one of amino acids 135- 143, based on the numbering of the MHC class I heavy chain polypeptide set forth in SEQ ID NO:6 (depicted in FIG. IF), and wherein amino acid 84, based on the numbering of the MHC class I heavy chain polypeptide depicted in FIG. IF, is other than Cys; and wherein each TMP comprises an intrachain disulfide bond between the Cys present in the peptide linker and the Cys at any one of amino acids 135-143 of the MHC class I heavy chain polypeptide, optionally wherein the MHC class I heavy chain polypeptide comprises a Cys at amino acid 138, 139, or 140 based on the numbering of the MHC class I heavy chain polypeptide set forth in SEQ ID NO:6 (depicted in FIG. IF), and optionally wherein the MHC class I heavy chain polypeptide comprises a Cys at amino acid 139 based on the numbering of the MHC class I heavy chain polypeptide set forth in SEQ ID NO: 6 (depicted in FIG. IF).33. The sealed container or plurality of sealed containers or means of aspect 31, wherein each TMP comprises an intrachain disulfide bond between the Cys present in the peptide linker and the Cys at amino acid 84 of the class I heavy chain polypeptide.34. The sealed container or plurality of sealed containers or means of any one of aspects 31-33, wherein each TMP comprises a Cys-containing peptide linker between the cancer-associated peptide and the 02M polypeptide, and wherein each TMP comprises an intrachain disulfide bond between the Cys present in the peptide linker and a Cys in the MHC class I heavy chain polypeptide, optionally wherein the peptide linker between the HPV peptide and the P2M polypeptide comprises the sequence CGGGS(GGGGS)n (SEQ ID NO: 61), GCGGS(GGGGS)n (SEQ ID NO: 62), or GGCGS(GGGGS)n (SEQ ID NO: 63), wherein n is an integer from 1-10.35. The sealed container or plurality of sealed containers or means of any one of aspects 25-34, wherein the P2M polypeptide comprises a Cys at amino acid 12, wherein the MHC class I heavy chain polypeptide comprises a Cys at amino acid 236, and wherein the TMP comprises aAttorney Docket No. 33194-0001 WO disulfide bond formed between the Cys at amino acid 12 of the P2M polypeptide and the Cys at amino acid 236 of the MHC class I heavy chain polypeptide.36. The sealed container or plurality of sealed containers or means of any one of aspects 1-35, wherein the two TMPs are identical, i.e., the DTMP is a homodimer.37. The sealed container or plurality of sealed containers or means of aspects 1-3, wherein each TMP comprises a peptide that is conjugated to a chemical conjugation site in the TMP, optionally wherein the P2M polypeptide, the one or more immunomodulatory polypeptides, the class I MHC heavy chain polypeptide, the Ig Fc polypeptide, and linkers are in a single polypeptide chain, and optionally wherein the chemical conjugation site is a cysteine in the P2M polypeptide.38. The sealed container or plurality of sealed containers or means of any aspect 37, wherein the two TMPs are identical, i.e., the DTMP is a homodimer, and wherein the two TMPs are joined by two disulfide bonds formed between the Ig Fc polypeptide of the first TMP and the Ig Fc polypeptide of the second TMP.39. The sealed container or plurality of sealed containers or means of any one of aspects 1-38, wherein the HPV peptide is an HPV16 peptide.40. The sealed container or plurality of sealed containers or means of aspect 39, wherein the HPV16 peptide comprises an HPV16 E6 epitope, optionally wherein the HPV16 peptide is selected from E6 18-26 (KLPQLCTEL; SEQ ID NO:25); E6 26-34 (LQTTIHDII; SEQ ID NO:26); E6 49-57 (VYDFAFRDL; SEQ ID NO:27); E6 52-60 (FAFRDLCIV; SEQ ID NO:28); E6 75-83 (KFYSKISEY; SEQ ID NO:29); and E6 80-88 (ISEYRHYCY; SEQ ID NO:30), or wherein the HPV peptide comprises an HPV16 E7 epitope, optionally wherein the cancer- associated peptide is selected from E7 7-15 (TLHEYMLDL; SEQ ID NO:31); E7 11-19(YMLDLQPET; SEQ ID NO:32); E7 11-20 (YMLDLQPETT; SEQ ID NO:20); E7 44-52(QAEPDRAHY; SEQ ID NO:33); E7 49-57 (RAHYNIVTF; (SEQ ID NO:34); E7 61-69(CDSTLRLCV; SEQ ID NO:35); E7 67-76 (LCVQSTHVDI; SEQ ID NO:36); E7 82-90(LLMGTLGIV; SEQ ID NO:37); E7 86-93 (TLGIVCPI; SEQ ID NO:38); and (LLMGTLGIVCPI; SEQ ID NO:39), optionally wherein the cancer-associated peptide is E7 11-20 (YMLDLQPETT; SEQ ID NO:20).Attorney Docket No. 33194-0001 WO41. The sealed container or plurality of sealed containers or means of any one of aspects 1-40, wherein the DTMP is CUE-101.42. A method of treating an HPV positive cancer in a human patient in need thereof comprising administering to said patient the means of any one of aspects 3-41 for treating said cancer in said patient.43. A method of treating cancer in a human patient in need of such treatment comprising administering to said patient a fixed dose of a DTMP according to any one of aspects 1- 41, wherein the cancer is an HPV-positive cancer, wherein the patient is administered a fixed dose that is irrespective of the weight of the patient, i.e., the dose administered to the patient is not dependent on, or adjusted for, the weight of the patient.44. A method of treating cancer in a human patient in need of such treatment comprising administering to said patient a fixed dose of a DTMP according to any one of aspects 39-42, wherein the cancer is an HPV 16-positive (HPV16+) cancer, and the patient is administered a fixed dose that is irrespective of the weight of the patient, i.e., the dose administered to the patient is not dependent on, or adjusted for, the weight of the patient, optionally wherein at least one TMP of the DTMP further comprises a targeting polypeptide that binds to an antigen on an HPV16- positive cancer cell.45. The method of aspect 44, wherein the HPV16+ cancer is a newly diagnosed HPV16+ head and neck cancer, or is a recurrent and / or metastatic HPV16+ head and neck cancer.46. The method of aspect 44, wherein the HPV16+ head and neck cancer is an oropharynx squamous cell cancer.47. The method of aspect 44, wherein the HPV16+ head and neck cancer is an oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, or laryngeal cancer.48. The method of aspect 44, wherein the HPV16+ cancer is penile cancer.49. The method of aspect 44, wherein the HP VI 6+ cancer is anal cancer.50. The method of aspect 44, wherein the HPV16+ cancer is vaginal cancer.Attorney Docket No. 33194-0001 WO51. The method of aspect 44, wherein the HPV16+ cancer is vulvar cancer.52. The method of aspect 44, wherein the HPV16+ cancer is cervical cancer.53. The method of any one of aspects 44-52, wherein the fixed dose of DTMP is administered to an individual who (i) had no prior therapies following an initial diagnosis of HPV16+ cancer, (ii) had at least one prior therapy following an initial diagnosis of HPV16+ cancer and was determined to have progressive disease, (iii) is receiving the composition as a neoadjuvant therapy for an HPV16+ cancer, (iv) is receiving the composition as a adjuvant therapy for an HPV16+ cancer, (v) is receiving the composition as a first line treatment following a diagnosis of recurrent and / or metastatic HPV16+ cancer, (vi) is receiving the composition as a second line or beyond therapy following a diagnosis of recurrent and / or metastatic HPV16+ cancer and a diagnosis of progressive disease following the patient’s prior line of treatment, or (vii) has become refractory to a prior treatment for an HPV 16+ cancer, has failed to respond to a prior treatment for an HPV 16+ cancer, and / or has been determined to have progressive disease following a prior treatment for an HPV 16+ cancer, optionally wherein the determination of progressive disease is based on RECIST 1.1 criteria, iRECIST criteria, or irRECIST criteria.54. The method of any one of aspects 43-53, wherein the fixed dose of DTMP is administered as an injectable.55. The method of aspect 54, wherein the fixed dose of DTMP is administered subcutaneously, intraperitoneally, intramuscularly, and / or intravenously.56. The method of any one of aspects 53-55, wherein the fixed dose of DTMP is administered every three weeks or every six weeks, optionally wherein the patient is already receiving a therapy other than a neoadjuvant therapy.57. The method of any one of aspects 43-56, wherein the cancer is associated with a PD-L1 Combined Positive Score (PD-L1 CPS) that is from 1-19, or from 20-100.58. The method of any one of aspects 43-56, wherein the cancer is associated with a PD-L1 CPS that is either 0 or more than 0 but less than 1.Attorney Docket No. 33194-0001 WO59. The method of aspect 57 or 58, wherein the PD-L1 CPS is determined by an Approved Laboratory using:(i) a PD-L1 IHC 22C3 pharmDx assay or an assay that employs a monoclonal mouse anti-PD-Ll antibody, clone 22C3;(ii) a PD-L1 IHC 28-8 pharmDx assay or an assay that employs a monoclonal mouse anti-PD-Ll antibody, clone 28-8; or(iii) an assay other than (i) or (ii).60. The method of any one of aspects 43-59, further comprising administering an immune checkpoint inhibitor (CPI) to a patient in need thereof, wherein the DTMP and checkpoint inhibitor are administered at the same time or at different times.61. The method of aspect 60, wherein the immune checkpoint inhibitor comprises an antibody that binds to a polypeptide selected from the group consisting of CD27, CD28, CD40, CD122, CD96, CD73, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137, ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, CD122, PD-1, PD-L1, and PD-L2.62. The method of aspect 61, wherein the immune checkpoint inhibitor comprises an antibody specific for PD-1, PD-L1, CTLA-4, LAG3, or TIGIT,63. The method of aspect 62, wherein the checkpoint inhibitor comprises an antibody specific for CTLA-4.64. The method of aspect 63, wherein the antibody is ipilimumab or tremelimumab.65. The method of aspect 62, wherein the checkpoint inhibitor comprises an antibody specific for LAG3.66. The method of aspect 62, wherein the checkpoint inhibitor comprises an antibody specific for TIGIT.67. The method of aspect 62, wherein the CPI comprises an antibody that binds PD-1.Attorney Docket No. 33194-0001 WO68. The method of aspect 67, wherein the CPI is pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, or tislelizumab.69. The method of aspect 67, wherein the CPI is pembrolizumab and is administered in an amount of 200 mg every three weeks or 400 mg every six weeks.70. The method of aspect 67, wherein the CPI is nivolumab and is administered in an amount of 240 mg every 2 weeks or 480 mg every 4 weeks.71. The method of any one of aspects 67-70, wherein the CPI is administered subcutaneously, optionally wherein the CPI is pembrolizumab or nivolumab.72. The method of aspect 67, wherein the CPI is cemiplimab.73. The method of aspect 67, wherein the CPI is dostarlimab, retifanlimab, toripalimab, or tislelizumab.74. The method of aspect 62, wherein the CPI is an antibody that binds PD-L1, optionally wherein the CPI is atezolizumab, avelumab, or durvalumab.75. The method of any one of aspects 43-59, further comprising administering to the patient a multi-specific antibody (e.g., a bispecific antibody) or multi-target fusion protein that binds to at least one immune checkpoint, wherein the fixed dose of DTMP and multi-specific antibody (e.g., bispecific antibody) or a multi-target fusion protein are administered at the same time or at different times.76. The method of aspect 75, wherein the multi-specific antibody (e.g., bispecific antibody) or a multi-target fusion protein binds to at least one of PD-1, PD-L1, CTLA-4, TIGIT, PVRIG and / or CD96.77. The method of aspect 74 or 75, wherein the multi-specific antibody (e.g., bispecific antibody) or multi -target fusion protein additionally binds to non-CPI target, e.g., VEGF, VEGF-A, a VEGF receptor (e g., VEGFR-1, VEGFR-2 or VEGFR-3), 4-1BB, or TGF-p.Attorney Docket No. 33194-0001 WO78. The method of aspect 76, wherein the multi-specific antibody (e.g., bispecific antibody) antibody or multi-target fusion protein binds to (i) PD-1 or PD-L1, and (ii) VEGF, VEGF- A, or VEGFR1.79. The method of aspect 76, wherein the patient is administered a bispecific antibody that binds to (i) PD-1 or PD-L1, and (ii) VEGF.80. The method of aspect 75, wherein the multi-specific (e.g., bispecific) antibody or multi-target fusion protein is BNT327, PM1009, PM1022, PM8001, PM1003, LM-299, Ivonescimab, SSGJ-707, AP505, JS207, Palverafusp alfa, RC148, Sotiburafusp alfa, AI-081, MHB039A, MK-2010, CVL006, or SGI408.81. The method of any one of aspects 42-80, further comprising the administration to said patient of a compound that directly binds HPV E5 protein.82. The method of aspect 81 , wherein the DTMP and the compound that binds HPV E5 protein are administered at the same time or at different times.83. The method of aspect 81 or 82, wherein the compound that binds HPV E5 protein is TGN-S11, TGN-S15, or a derivative of TGN-S11 or TGN-S15.84. A kit for treating a patient with an HPV16+ cancer, the kit comprising:(a) the sealed container or plurality of sealed containers (e.g. vials) according to any one of aspects 1-41; and(b) instructions for using the fixed dose of DTMP in the method of any one of aspects 44-83.85. The kit of aspect 84, wherein the fixed dose of DTMP comprises from 135 to 165 mg of DTMP, optionally wherein the fixed dose is 150 mg.86. The kit of aspect 84, wherein the fixed dose of DTMP comprises from 270 to 330 mg of DTMP, optionally wherein the fixed dose is 300 mg.87. The kit of aspect 84, wherein the fixed dose of DTMP comprises from 135 to 330 mg of DTMP, optionally wherein the fixed dose is 150 mg or 300 mg.Attorney Docket No. 33194-0001 WO88. Use of the DTMP of one of aspects 1-41, or the kit of any one of aspect 84-87 for treating an individual having an HPV+ cancer.89. Use of the DTMP of one of aspects 1-41 in the preparation of a medicament for treating an individual having an HPV+ cancer.90. The sealed container or plurality of sealed containers or means of any one of aspects 1-41 for the treatment of an individual having an HPV+ cancer.91. The use of aspect 88 or 89, or the sealed container or plurality of sealed containers or means of aspect 90, wherein the HPV cancer is an HPV16+ cancer, and wherein the HPV16+ cancer is an oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer, penile cancer, anal cancer, vaginal cancer, vulvar cancer, or cervical cancer.92. A method of treating an HPV positive cancer in a human patient in need thereof comprising administering to said patient the means of any one of aspects 3-41 for treating said cancer in said patient.93. A method of treating a patient who is receiving a cellular therapy composition, the method comprising: i) administering to the patient a plurality CAR-T cells or TCR-T cells that comprise a target T-cell receptor (TCR), and ii) administering to the patient a fixed dose of a DTMP according to any one of aspects 1-41, wherein the DTMP comprises a pMHC that specifically binds to the target TCR, wherein the administration of (i) the CAR-T cells or TCR-T cells and (ii) the fixed dose of DTMP can occur at the same time or different times.94. A method according to aspect 93, wherein the patient is administered fixed doses of DTMP periodically following the administration of the CAR-T cells or TCR-T cells.95. A kit comprising (i) the sealed container or plurality of sealed containers of any one of aspects 1-41, and (ii) instructions for administering a fixed dose of the DTMP to a patient in need thereof who has also received an administration of CAR-T cells or TCR-T cells having a target TCR, wherein the DTMP comprises a pMHC that specifically binds to the target TCR.Attorney Docket No. 33194-0001 WO96. A kit comprising (i) the sealed container or plurality of sealed containers of any one of aspects 1-41, and (ii) instructions for administering a fixed dose of the DTMP to a patient in need thereof.97. The kit of aspect 95 or 96, wherein the fixed dose of the DTMP is: i) from about 25 mg to about 135 mg, from about 50 mg to about 125 mg, from about 75 mg to about 100 mg, from about 135 mg to about 330 mg, from about 150 to about 300 mg, from about 135 mg to about 165 mg, from about 165 mg to about 270 mg, from about 270 mg to about 330 mg, from about 350 to about 400 mg, or from about 450 mg to about 495 mg, or ii) from 25 mg to 135 mg, from 50 mg to 125 mg, from 75 mg to 100 mg, from 135 mg to 330 mg, from 150 to 300 mg, from 135 mg to 165 mg, from 165 mg to 270 mg, or from 270 mg to 330 mg, from 350 to 400 mg, or from 450 mg to 495 mg, or iii) 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, or 330 mg, or iv) about 350 mg, 350 mg, about 375 mg, 375 mg, about 400 mg, 400 mg, about 425 mg, 425 mg, about 450 mg, or 450 mg.98. The kit of aspect 95 or 96, wherein the fixed dose of the DTMP is selected from 150 mg, 225 mg, and 300 mg.99. The kit of aspect 95 or 96, wherein the fixed dose of the DTMP is from 25 mg to 135 mg, optionally wherein the fixed dose is 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, or 135 mg.100. The kit of aspect 95 or 96, wherein the fixed dose of the DTMP is from about 350 to 400 mg, from about 450 to 495 mg, from 350 to 400 mg, or from 450 mg to 495 mg, optionallyAttorney Docket No. 33194-0001 WO wherein the fixed dose is about 350 mg, 350 mg, about 375 mg, 375 mg, about 400 mg, 400 mg, about 425 mg, 425 mg, about 450 mg, or 450 mg.Aspect Section B1. A sealed container comprising a fixed dose of a dimeric T cell modulatory protein (DTMP), or a plurality of sealed containers, each comprising a predetermined portion of a fixed dose of a DTMP, wherein the DTMP comprises two T cell modulatory proteins (TMPs), wherein each TMP comprises the following components: a) a first polypeptide comprising: i) a human papillomavirus epitope, wherein the epitope comprises the amino acid sequence YMLDLQPETT (SEQ ID NO:20); and ii) a first major histocompatibility complex (MHC) polypeptide, wherein the first MHC polypeptide is a p2-microglobulin (02M) polypeptide comprising an amino acid sequence as set forth in SEQ ID NO: 17, and b) a second polypeptide comprising: i) two copies of an IL-2 polypeptide, each copy comprising an amino acid sequence set forth in SEQ ID NO:22; iii) a second MHC polypeptide, wherein the second MHC polypeptide is an MHC class I heavy chain polypeptide comprising an amino acid sequence as set forth in SEQ ID NO: 19; and iv) an immunoglobulin (Ig) Fc polypeptide, optionally wherein the first polypeptide and the second polypeptide are covalently linked to one another via a disulfide bond, wherein the heterodimers are linked by two disulfide bonds that join the Ig Fc polypeptide of one heterodimer to the Ig Fc polypeptide of the other heterodimer, wherein the fixed dose of the DTMP is not based on the weight of any one individual patient, and wherein the fixed dose of the DTMP is from 135 mg to 330 mg, from 150 to 300 mg, from 135 mg to 165mg, from 165 mg to 270 mg, or from 270 mg to 330 mg.Attorney Docket No. 33194-0001 WO2. A sealed container comprising a fixed dose of a dimeric T cell modulatory protein (DTMP), or a plurality of sealed containers, each comprising a predetermined portion of a fixed dose of a DTMP, wherein the DTMP comprises two T cell modulatory proteins (TMPs), wherein each TMP comprises the following components: a) a first polypeptide comprising: i) a human papillomavirus epitope, wherein the epitope comprises the amino acid sequence YMLDLQPETT (SEQ ID NO:20); and ii) a first major histocompatibility complex (MHC) polypeptide, wherein the first MHC polypeptide is a p2-microglobulin (P2M) polypeptide comprising an amino acid sequence as set forth in SEQ ID NO: 17, and b) a second polypeptide comprising: i) two copies of an IL-2 polypeptide, each copy comprising an amino acid sequence set forth in SEQ ID NO:22; iii) a second MHC polypeptide, wherein the second MHC polypeptide is an MHC class I heavy chain polypeptide comprising an amino acid sequence as set forth in SEQ ID NO: 19; and iv) an immunoglobulin (Ig) Fc polypeptide, wherein the first polypeptide and the second polypeptide are covalently linked to one another via a disulfide bond, wherein the fixed dose of the DTMP is not based on the weight of any one individual patient, and wherein the fixed dose of the DTMP is 150 mg or 300 mg.3. A method of treating cancer in a human patient in need of such treatment comprising administering to said patient a fixed dose of DTMP according to aspect 1 or 2, wherein the cancer is an HPV16-positive cancer, and wherein the patient is administered a dose that is irrespective of the weight of the patient, i.e., the dose administered to the patient is not dependent on, or adjusted for, the weight of the patient.4. The method of aspect 3, wherein the cancer is a newly diagnosed HPV16+ head and neck cancer, or is a recurrent and / or metastatic HPV16+ head and neck cancer.Attorney Docket No. 33194-0001 WO5. The method of aspect 4, wherein the HPV16+ head and neck cancer is an oropharynx squamous cell cancer.6. The method of aspect 4 wherein the HPV16+ head and neck cancer is an oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, or laryngeal cancer.7. The method of aspect 3, wherein the HPV16+ cancer is penile cancer.8. The method of aspect 3, wherein the HPV16+ cancer is anal cancer.9. The method of aspect 3, wherein the HPV16+ cancer is vaginal cancer.10. The method of aspect 3, wherein the HPV16+ cancer is vulvar cancer.11. The method of aspect 3, wherein the HPV16+ cancer is cervical cancer.12. The method of any one of aspects 3-11, wherein the fixed dose of DTMP is administered to an individual who (i) had no prior therapies following an initial diagnosis of HPV16+ cancer, (ii) had at least one prior therapy following an initial diagnosis of HPV16+ cancer and was determined to have progressive disease, (iii) is receiving the composition as a neoadjuvant therapy for an HPV16+ cancer, (iv) is receiving the composition as an adjuvant therapy for an HPV16+ cancer, (v) is receiving the composition as a first line treatment following a diagnosis of recurrent and / or metastatic HPV16+ cancer, (vi) is receiving the composition as a second line or beyond therapy following a diagnosis of recurrent and / or metastatic HPV16+ cancer and a diagnosis of progressive disease following the patient’s prior line of treatment, or (vii) has become refractory to a prior treatment for an HPV16+ cancer, has failed to respond to a prior treatment for an HPV16+ cancer, and / or has been determined to have progressive disease following a prior treatment for an HPV 16+ cancer, optionally wherein the determination of progressive disease is based on RECIST 1.1 criteria, iRECIST criteria, or irRECIST criteria.13. The method of any one of aspects 3-12, wherein the fixed dose of DTMP is administered as an injectable.14. The method of aspect 13, wherein the fixed dose of DTMP is administered subcutaneously, intraperitoneally, intramuscularly, or intravenously.Attorney Docket No. 33194-0001 WO15. The method of any one of aspects 3-14, wherein the fixed dose of DTMP is administered every three weeks or every six weeks, and wherein the patient is receiving a therapy other than a neoadjuvant therapy.16. The method of any one of aspects 3-15, wherein the cancer is associated with a PD- L1 Combined Positive Score (PD-L1 CPS) that is from 1-19 or from 20-100.17. The method of any one of aspects 3-15, wherein the cancer is associated with a PD- L1 CPS that is either 0 or more than 0 but less than 1.18. The method of aspect 16 or 17, wherein the PD-L1 CPS is determined by an Approved Laboratory using:(i) a PD-L1 IHC 22C3 pharmDx assay or an assay that employs a monoclonal mouse anti-PD-Ll antibody, clone 22C3;(ii) a PD-L1 IHC 28-8 pharmDx assay or an assay that employs a monoclonal mouse anti-PD-Ll antibody, clone 28-8; or(iii) an assay other than (i) or (ii).19. The method of any one of aspects 3-18, further comprising administering an immune checkpoint inhibitor (CPI) to the patient, wherein the fixed dose of DTMP and checkpoint inhibitor are administered at the same time or at different times.20. The method of aspect 19, wherein the immune checkpoint inhibitor is an antibody that binds to a polypeptide chosen from CD27, CD28, CD40, CD 122, CD96, CD73, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137, ICOS, A2AR, B7-H3, B7- H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, CD122, PD-1, PD-L1, and PD-L2.21. The method of aspect 20, wherein the immune checkpoint inhibitor is an antibody specific for PD-1, PD-L1, CTLA-4, LAG3, or TIGIT,22. The method of aspect 21, wherein the checkpoint inhibitor is an antibody specific for CTLA-4.23. The method of aspect 22, wherein the antibody is ipilimumab or tremelimumab.Attorney Docket No. 33194-0001 WO24. The method of aspect 21, wherein the checkpoint inhibitor is an antibody specific for LAG3.25. The method of aspect 21, wherein the checkpoint inhibitor is an antibody specific for TIGIT.26. The method of aspect 20, wherein the CPI is an antibody that binds PD-1.27. The method of aspect 26, wherein the CPI is pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, or tislelizumab.28. The method of aspect 27, wherein the CPI is pembrolizumab and is administered in an amount of 200 mg every three weeks or 400 mg every six weeks.29. The method of aspect 27, wherein the CPI is nivolumab and is administered in an amount of 240 mg every 2 weeks or 480 mg every 4 weeks.30. The method of any one of aspects 26-29, wherein the CPI is administered subcutaneously, optionally wherein the CPI is pembrolizumab or nivolumab.31. The method of aspect 20, wherein the CPI is an antibody that binds PD-L1.32. The method of aspect 31, wherein the CPI is atezolizumab, avelumab, or durvalumab.33. The method of aspect 31, wherein the CPI is avelumab, or durvalumab.34. The method of any one of aspects 3-18, further comprising administering to the patient a multi-specific antibody (e.g., a bispecific antibody) or a multi-target fusion protein that binds to at least one immune checkpoint, wherein the fixed dose of DTMP and multi-specific antibody (e.g., bispecific antibody) or a multi-target fusion protein are administered at the same time or at different times.35. The method of aspect 34, wherein the multi-specific antibody (e g., bispecific antibody) or a multi-target fusion protein binds to at least one of PD-1, PD-L1, CTLA-4, TIGIT, PVRIG and / or CD96.Attorney Docket No. 33194-0001 WO36. The method of aspect 34 or 35, wherein the multi-specific antibody (e.g., bispecific antibody) or multi-target fusion protein additionally binds to non-CPI target, e.g., VEGF, VEGF-A, a VEGF receptor (e.g., VEGFR-1, VEGFR-2 or VEGFR-3), 4-1BB, or TGF-0.37. The method of aspect 36, wherein the multi-specific antibody (e g., bispecific antibody) antibody or multi-target fusion protein binds to (i) PD-1 or PD-L1, and (ii) VEGF, VEGF- A, or VEGFRl .38. The method of aspect 36, wherein the patient is administered a bispecific antibody that binds to (i) PD-1 or PD-L1, and (ii) VEGF.39. The method of aspect 35, wherein the multi-specific (e.g., bispecific) antibody or multi-target fusion protein is BNT327, PM1009, PM1022, PM8001, PM1003, LM-299, Ivonescimab, SSGJ-707, AP505, JS207, Palverafusp alfa, RC148, Sotiburafusp alfa, AI-081, MHB039A, MK-2010, CVL006, or SGI408.40. The method of any one of aspects 3-39, further comprising the administration to said patient a plurality of cytotoxic T cells, wherein the plurality comprises CAR-T cells that comprise a receptor that binds to an HPV antigen on a cancer cell.41. The method of any one of aspects 3-39, further comprising the administration to said patient a plurality of cytotoxic T cells, wherein the plurality comprises TCR-T cells comprise a T cell receptor that binds to an HPV antigen on a cancer cell.42. The method of aspect 40 or 41, wherein the fixed dose of DTMP and the plurality of cytotoxic T cells are administered at the same time or at different times.43. A kit compri sing :(a) a sealed container or a plurality of sealed containers according to aspect 1; and(b) instructions for administering a fixed dose of DTMP.44. The kit of aspect 43, wherein the fixed dose of DTMP is i) from about 25 mg to about 135 mg, from about 50 mg to about 125 mg, from about 75 mg to about 100 mg, from about 135 mg to about 330 mg, from about 150 to about 300 mg, from about 135 mg to about 165 mg, from about 165 mg toAttorney Docket No. 33194-0001 WO about 270 mg, from about 270 mg to about 330 mg, from about 350 to about 400 mg, from about 450 mg to about 495 mg, or ii) from 25 mg to 135 mg, from 50 mg to 125 mg, from 75 mg to 100 mg, from 135 mg to 330 mg, from 150 to 300 mg, from 135 mg to 165 mg, from 165 mg to 270 mg, or from 270 mg to 330 mg, from 350 to 400 mg, or from 450 mg to 495 mg.45. The kit of aspect 43, wherein the fixed dose of DTMP is 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, or 330 mg.46. The kit of aspect 43, wherein the fixed dose of DTMP is about 350 mg, 350 mg, about 375 mg, 375 mg, about 400 mg, 400 mg, about 425 mg, 425 mg, about 450 mg, or 450 mg.47. A kit for treating a patient with an HPV 16+ cancer, the kit comprising:(a) the sealed container or plurality of sealed containers (e.g. vials) according to aspect 1; and(b) instructions for using the fixed dose of DTMP in the method of any one of aspects 3-42.48. The kit of aspect 47, wherein the wherein the fixed dose of DTMP is 150 mg.49. The kit of aspect 47, wherein the fixed dose of DTMP is 225 mg.50. The kit of aspect 47, wherein the fixed dose of DTMP is 300 mg.51. Use of the sealed container or a plurality of sealed containers of aspect 1 or 2, or the kit of any one of aspects 43-50 for treating an individual suffering from an HPV+ cancer.52. Use of the sealed container or a plurality of sealed containers of aspect 1 or 2, or the kit of any one of aspects 43-50 for the preparation of a medicament for treating an individual suffering from an HPV+ cancer.Attorney Docket No. 33194-0001 WO53. The use of aspect 51 or 52, wherein the HPV 16+ cancer is an oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer, penile cancer, anal cancer, vaginal cancer, vulvar cancer, or cervical cancer.54. The sealed container or plurality of sealed containers (e.g. vials) according to aspect 1 or 2, wherein the DTMP is CUE-101.55. The method of any one of aspects 3-42, wherein the DTMP is CUE-101.56. The kit according to any one of aspects 43-50, wherein the DTMP is CUE-101.57. The use according to any one of aspects 51-53, wherein the DTMP is CUE-101.EXAMPLES

[0159] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the fixed doses and methods of this disclosure, and are not intended to limit the scope of what the inventors regard as their invention set forth in the appended claims.Example 1: Comparison of Weight-Based Doses (mg / kg) and Fixed DosesINTRODUCTION

[0160] One study of CUE-101, CUE-101-01 (NCT03978689) is a first-in-human (FIH) Phase I, open label, 4-part dose escalation / expansion study for evaluation of safety, tolerability, antitumor activity, immune response, pharmacokinetics (PK) and biomarkers of response in patients with advanced head and neck squamous cell carcinoma (HNSCC).

[0161] The objectives of these analyses are as follows:• Develop and qualify a preliminary population pharmacokinetic (PK) model of CUE-101 in HNSCC patients.• Perform simulations from the PK model to assess fixed-dose vs weight-based dosing.Attorney Docket No. 33194-0001 WOMETHODSStudy Design

[0162] Study CUE-101-01 is a first-in-human, open label, dose escalation and expansion study of CUE-101 monotherapy in second line and CUE-101 combination therapy with pembrolizumab in first line patients with HPV16+ recurrent / metastatic head and neck squamous cell carcinoma (HNSCC). The trial consists of 4 parts: (A) CUE-101 monotherapy dose escalation, (B) CUE-101 monotherapy dose expansion / confirmation, (C) combination dose escalation, and (D) combination dose expansion / confirmation, in which CUE-101 is administered intravenously over one hour every 3 weeks. In the preliminary analyses in this Example 1, only Parts A, B, & C were included because as the time of the analyses, the current first-in-human study was still accruing patients in Part D.Pharmacokinetic Modelling

[0163] A population pharmacokinetic model was developed using CUE-101 drug concentrations collected over multiple cycles in Parts A, B, and C of the trial. The drug was given as monotherapy with doses ranging from 0.06 mg / kg to 8 mg / kg in Parts A and B to a total of 49 subjects, and as a combination with 200 mg pembrolizumab with CUE-101 doses ranging from 1 mg / kg to 4 mg / kg in Part C to a total of 9 subjects as of the data cut-off for this analysis. Serum concentrations of CUE- 101 were determined using a validated hybrid capture LC / MS / MS assay that simultaneously measures two unique peptides from CUE-101. Based on exposure similarity of both peptides, only the MHC I E7 (referred to as E7) peptide concentrations were used for this analysis. All available E7 concentration data from all cycles were used in model building.

[0164] Different structural models were evaluated based on the trends that were observed in the preliminary concentrati on-time plots (not shown). The base pharmacokinetic models were evaluated using the following:• Successful model convergence / minimization.• Akaike information criterion (AIC): A statistical measure used to compare non-nested models (e g., between 2 and 3 compartment models).• Relative standard error (%RSE): a metric used to evaluate the precision of the parameter estimates.• Goodness of fit plots:Attorney Docket No. 33194-0001 WO o Observations vs. population prediction (PRED) (linear and natural log scale), o Observations vs. individual population prediction (IPRED) (linear and natural log scale), o Conditional Weighted Residuals (CWRES) vs PRED, o Conditional Weighted Residuals (CWRES) vs TIME.• Histograms of the individual empirical bayes estimates of each parameter.• Histograms of ETAs.• Pairwise plots of ETAs. According to the European Medicines Agency (EMA), an ETA is a “random effect describing the deviation of the individual empirical Bayes estimate of the parameter from the typical population parameter estimate.”• Individual DV (Dependent variable, i.e., observed E7 concentrations), PRED (Population predictions of E7 concentrations based on the population estimates of the model), IPRED (Individual predictions of E7 concentrations based on the individual estimates of the model) vs. time for each subject.• Normalized prediction distribution error (NPDE) vs. comparison to standard normal distribution.

[0165] Information about total body weight, sex, and the combination therapy (pembrolizumab) were available for the studied population. These covariates were handled as the following:• Weight was assumed as a covariate on all PK parameters of the model (except duration of infusion). Clearance, intercompartmental clearance and volume values were allometrically scaled to a median body weight of 77.7 kg, with a fixed exponent of % for clearance and intercompartmental clearance, and 1 for volume.• Sex was not evaluated as a covariate because only 2 females were enrolled in the study.• ETA vs. pembrolizumab diagnostic plots were used to investigate the relationships between pembrolizumab and the PK model parameters (except duration of infusion). This was done after ensuring that no significant ETA shrinkage has occurred.

[0166] The predictive performance of the final pharmacokinetic model was evaluated using posterior predictive checks (PPC), where a PK statistic such as the AUC (area under the curve) orAttorney Docket No. 33194-0001 WOCmax (maximum concentration) are calculated from the observed data and then compared to its distribution that was generated from final model simulations. In this analysis, AUC (0 to infinity) and Cmax obtained from cycle 1 were used as this cycle included the highest number of samples post-dose.

[0167] Approximately 18.5% of the PK data (drug concentrations measured as E7) were below the limit of quantification (BLQ) of the method (< 10 ng / ml). Method M3 (a method that maximizes the likelihood for BLQ data) was applied to handle such data as it generates the least biased results compared to other known methods used to handle BLQ data. The bias, if no appropriate method to handle BLQ is applied, could be in the structure of the model and / or parameter estimates.

[0168] Drug concentration data points that appeared to not fit with the models under investigation were not automatically excluded. For example, drug concentrations that were found to be inappropriately low or high, or suspected errors in recorded sampling times, were commented out of the NONMEM datafiles (i.e., not used in the analysis). If no reason was found for outlier data points, these data points were kept in the analysis unless their inclusion directly impacted either the convergence of the models or resulted in biologically implausible parameter estimates. The outlier detection criterion was set to conditional weighted residuals (CWRES) > 6 for the sample but may have been changed based on the assessment of the goodness of fit and the model parameter estimates.Pharmacokinetic Simulations of weight-based doses (mg / kg) and fixed doses (mg)

[0169] Monte Carlo simulations using the final population pharmacokinetic model were performed to obtain simulated drug concentrations after administration of weight-based doses and fixed doses of CUE-101 for the simulated population. Datasets of simulated populations consisting of 1000 adults having weight (kg) (mean = 80 kg, standard deviation = 20 kg, maximum weight = 138.88 kg, and minimum weight = 40.06 kg) as the only covariate were created. The selected criteria for the simulated weight were based on the actual body weight distribution amongst the patients treated in study CUE-101 -01. The same simulated population was used for each tested dose (fixed or weight-based dose) to exclude the effect of different weights (from different simulated populations) on the tested doses. A list of the tested doses is presented in Table. Fixed doses were selected by multiplying a low weight-based dose (0.5 mg / kg) with a low observed weight (kg) and by multiplying a high weight-based dose (4 mg / kg) with a high observed weight (kg) in the studied population. The simulated concentrations of weight-based doses and fixed dose of CUE- 101 were then used to calculate the exposure metrics AUC (calculated as dose over clearance) and Cmax. TheAttorney Docket No. 33194-0001 WO proportionality of CUE-101 weight -based doses and fixed doses were then assessed with the obtained exposures. The two dosing methods were then graphically compared in terms of AUC and Cmax exposures.Table 1: Fixed doses (mg) and weight-based doses (mg / kg)Software

[0170] Nonlinear mixed-effects modelling and simulations were executed by PDx-Pop 5.3 using NONMEM 7.5. Statistical and graphical analyses were conducted using R version 4.2.1.RESULTSPharmacokinetic Model

[0171] Both 2-compartment and 3 -compartment models were fit to the E7 concentration-time data. These models are depicted in FIG. 2. The 3 -compartment model best described the data according to the evaluation methods utilized in this study.

[0172] The 3 -compartment model consisted of a central compartment with volume of distribution (VI), into which the IV drug is administered and from which the elimination by first order clearance (CL) occurs. It also had two peripheral compartments with V2 and V3. The drug transfer between the central and peripheral compartments is characterized by intercompartmental clearances (QI and Q2). The AIC estimates were 457.847 and -41.619 for the 2- and 3-compartment models, respectively. The lower AIC value for the 3-compartment model suggests that it provides a significantly better fit to the data. Further, goodness of fit plots shown in FIGS. 3A-FError! Reference source not found, (shown only for 3-compartment model) suggests that this model described the data well, as shown by even scatter around the unity line in the population and individual prediction and a lack of systematic deviation from the zero line in the conditional weighted residuals.

[0173] FIGS. 3A-3F illustrate basic goodness of fit plots for the final preliminary population PK model. FIG. 3A illustrates a log of observed E7 concentrations (ng / mL) vs. log of populationAttorney Docket No. 33194-0001 WO predicted E7 concentrations (ng / mL). FIG. 3B is the same as FIG. 3A, but the observations are in linear scale. FIG. 3C illustrates the log of observed E7 concentrations (ng / mL) vs. log of individual predicted E7 concentrations (ng / mL). FIG. 3D is the same as FIG. 3C, but the observations are in linear scale. FIG. 3E illustrates conditional weighted residuals vs population predicted E7 concentrations (ng / mL). FIG. 3F illustrates conditional weighted residuals vs time (hours). In FIGS. 3A, 3B, 3C, and 3D, the dashed line is the identity line and the solid line is the regression line. The points (dots) in FIGS. 3A and 3C are the log of observed E7 concentrations. The points in FIGS. 3B and 3D are the observed E7 concentrations. In FIGS. 3E and 3F, the dashed line is the zero-line, and the solid line is LOESS smoothing. The points in FIGS. 3E and 3F are the values of conditional weighted residuals.

[0174] Normalized prediction distribution errors (NPDE) were shown to follow the standard normal distribution (not shown).

[0175] A total of 1198 drug concentration data points for E7 were available for analysis. The data used for the final population PK model were handled as follows:• Included in the analysis: o 900 complete data points. o 207 BLQ data points.• Removed from the analysis: o 54 pre-first dose BLQ data points at C1D1. These were removed under the assumption that pre-first dose drug concentrations are equal to zero since the doses were still not administered to the patients. o 28 censored or missing data points (such as NRR, <20.0, <80.0, <400, <1000, or >40000). o 9 data points for various reasons. These points comprise approximately 0.8% of the total data (total data excluding the 54 pre-first dose and the 28 censored or missing data points).

[0176] Population pharmacokinetic parameter estimates for the 3-compartment population pharmacokinetic model are provided in Table 2. All estimates were precisely estimated according to the relative standard errors (%RSE) except for the variance estimate (presented as inter-individual variability (IIV) for duration of infusion (D). Low ETA shrinkage (6.57-17.4% SD) was observedAttorney Docket No. 33194-0001 WO with the parameter estimates of the model (except duration of infusion).Table 2: Parameter estimates for the 3-compartment population pharmacokinetic model

[0177] The posterior predictive checks (PPC) of AUC (0 to infinity) and Cmax of the final pharmacokinetic model are shown in FIGS. 4A and 4B, respectively. FIG 4A illustrates a posterior predictive check using AUC (0 to infinity) (normalized by dose) as the PK statistic. FIG. 4B illustrates a posterior predictive check using Cmax (normalized by dose) as the PK statistic. Vertical lines (from left to right): The dashed and solid vertical lines located at the far left of the histogram are the 5th percentiles of the simulated and observed AUC (0 to infinity), respectively. Dashed and solid vertical lines located at the middle of the histogram are the 50th percentiles of the simulated and observed AUC (0 to infinity), respectively. Dashed and solid vertical lines located at the far right of the histogram are the 95th percentiles of the simulated and observed AUC (0 to infinity), respectively. No major systematic discrepancies between the simulated and the observed AUC (0 to infinity) and Cmax were apparent.Attorney Docket No. 33194-0001 WOPharmacokinetic Simulations of weight-based doses (mg / kg) and fixed doses (mg)

[0178] Shown in FIG. 5 and FIG. 6 are the simulated exposures of AUC and Cmax, respectively, after the administration of fixed doses (mg) and weight-based doses (mg / kg) of CUE-101. The left plot in FIG. 5 illustrates the simulated AUC (mg*hr / L) for weight-based doses (mg / kg). The right plot in FIG. 5 illustrates simulated AUC (mg*hr / L) for fixed doses (mg). The left plot in FIG. 6 illustrates the simulated Cmax (mg / L) for weight-based doses (mg / kg). The right plot in FIG. 6 illustrates simulated Cmax (mg / L) for fixed doses (mg). Both exposures increase proportionally with CUE-101 fixed and weight-based doses. Higher variability in exposures was observed with the fixed doses as compared to the weight-based doses.

[0179] A more focused comparison between a weight-based dose of 4 mg / kg and a fixed dose of 300 mg of CUE-101 in terms of the simulated exposures of AUC and Cmax are shown in FIG. 7 and FIG. 8, respectively. The left plot in FIG. 7 illustrates simulated AUC (mg*hr / L) for a weight-based dose of 4 mg / kg. The right plot in FIG. 7 illustrates simulated AUC (mg*hr / L) for a fixed dose of 300 mg. The left plot in FIG. 8 illustrates simulated Cmax (mg / L) for a weight-based dose of 4 mg / kg. The right plot in FIG. 8 illustrates simulated Cmax (mg / L) for a fixed dose of 300 mg. Summary statistics of the simulated exposures of AUC and Cmax of these two doses are also presented in Table 3 and Table 4 below, respectively. It appears that a fixed dose of 300 mg would approximate the exposure of a weight-based dose of 4 mg / kg dose, with the fixed dose of 300 mg resulting in slightly higher variability (based on the standard deviations) in exposures compared to the weight-based dose of 4 mg / kg.Table 3: Summary statistics of the simulated AUC (mg*hr / L) from the weight-based dose of 4 mg / kg and the fixed dose of 300 mg.Attorney Docket No. 33194-0001 WOTable 4: Summary statistics of the simulated Cmax (mg / L) from the weight-based dose of 4 mg / kg and the fixed dose of 300 mg.CONCLUSIONS

[0180] CUE-101 disposition was best described by a 3-compartment model with elimination from the central compartment. Clearance of CUE-101 is low (1.10 L / hr for a 70 kg individual), with the volumes of distribution suggesting that there is some distribution into peripheral tissues. The overall fit to the observed data was very good, and the model predicted summary exposure metrics (AUC and Cmax) reasonably well.

[0181] Simulations examining the suitability of CUE-101 to be given by fixed doses suggest that a fixed dose of 300 mg would match the exposures seen at 4 mg / kg. The simulated exposures using fixed dosing appeared to be slightly more variable than those observed after weight-based dosing. This small increase in variability is unlikely to be clinically significant.Example 2; Comparison of Weight-Based Doses (2 and 4 mg / kg) and Fixed Doses 1150 and 300 mg)

[0182] Having determined (as discussed above) that 4 mg / kg weight-based dosing and a fixed dose of 300 mg provide comparable drug exposures of CUE-101, an analysis was performed to determine whether 2 mg / kg weight -based dosing and a fixed dose of 150 mg provide comparable exposures of CUE-101.

[0183] Monte Carlo simulations using the population pharmacokinetics model discussed above were performed to obtain simulated drug concentrations of CUE-101 after the administration of the following doses:• Weight-based doses: 2 and 4 mg / kg• Fixed doses: 150 and 300 mg

[0184] The simulated drug concentrations were used to calculate the exposure metrics AUCAttorney Docket No. 33194-0001 WO(mg*hr / L) and Cmax (mg / L). The same simulated population of 1000 adults (mean body weight = 80 kg, standard deviation = 20 kg, maximum weight = 138.88 kg, and minimum weight = 40.06 kg) was used for each dose to allow for an equivalent comparison. Summary statistics of the simulated Cmax (mg / L) and AUC (mg*hr / L) are presented in Tables 7 and 8, respectively. Slightly higher variability in exposure metrics (increased SD) was observed with the fixed doses of 150 and 300 mg as compared to the weight-based doses of 2 and 4 mg / kg. This small increase in variability is unlikely to be clinically significant.Table 7: Mean (SD), median, 90% CI, and entire range (min and max) of the simulated Cmax (mg / L).Table 8: Mean (SD), median, 90% CI, and entire range (min and max) of the simulated AUC (mg*hr / L).

[0185] FIG. 9 compares the distributions of the simulated Cmax (mg / L) of the fixed dose of 150 mg and the weight-based doses of 2 and 4 mg / kg. The area of both the weight-based dose of 2 mg / kg and the fixed dose of 150 mg are superimposed, with slightly higher variability observed with the fixed dose of 150 mg. In addition, the higher exposure Cmax (mg / L) values obtained with 2 mg / kg and 150 mg overlap with 4 mg / kg. There is a very similar degree of overlap between the 2 mg / kgAttorney Docket No. 33194-0001 WO and 150 mg dose, and 4 mg / kg.

[0186] FIG. 10 compares the distributions of the simulated Cmax (mg / L) of the fixed doses of 150 mg, 300 mg, and weight-based dose of 2 mg / kg. The results are similar to those seen in FIG. 9, in that the area of both the weight-based dose of 2 mg / kg and the fixed dose of 150 mg are superimposed with each other, with slightly higher variability observed with the fixed dose of 150 mg. In addition, the higher exposure Cmax (mg / L) values obtained with 2 mg / kg and 150 mg overlapped with the lower exposure values obtained with 300 mg. Similar to what was seen in FIG.10, there is a very similar degree of overlap between the 2 mg / kg and 150 mg dose, and 300 mg.

[0187] FIG. 11 compares the distributions of the simulated AUC (mg*hr / L) of the fixed dose of 150 mg and the weight-based doses of 2 and 4 mg / kg. The area of both the weight-based dose of 2 mg / kg and the fixed dose of 150 mg are superimposed, with slightly higher variability observed with the fixed dose of 150 mg. In addition, the higher exposure AUC (mg*hr / L) values obtained with 2 mg / kg and 150 mg overlap with 4 mg / kg. There is a very similar degree of overlap between the 2 mg / kg and 150 mg dose, and 4 mg / kg.

[0188] FIG. 12 compares the distributions of the simulated AUC (mg*hr / L) of the fixed doses of 150 mg, 300 mg, and weight-based dose of 2 mg / kg. The results are similar to those seen in FIG. 11 in that the area of both the weight-based dose of 2 mg / kg and the fixed dose of 150 mg are superimposed with each other, with slightly higher variability observed with the fixed dose of 150 mg. In addition, the higher AUC (mg*hr / L) exposure values obtained with 2 mg / kg and 150 mg overlapped with the lower exposure values obtained with 300 mg. Similar to what was seen in FIG.11, there is a very similar degree of overlap between the 2 mg / kg and 150 mg dose, and 300 mg.CONCLUSIONS

[0189] Both a weight-based dose of 2 mg / kg and a fixed dose of 150 mg yield very similar exposure values (Cmax and AUC). A weight-based dose of 4 mg / kg and a fixed dose of 300 mg also lead to very similar exposures, as discussed above.

[0190] Although disposition of a drug can be affected by a number of factors, including body weight, based on the data discussed above, body weight does not appear to be a covariant for CUE- 101 drug exposure, and thus disposition of CUE-101 appears to be independent, or at least substantially independent of body weight.Attorney Docket No. 33194-0001 WOExample 3: Comparison of the PK Profiles of Two Different TMPs

[0191] Drug concentration-time profiles of a first homodimeric TMP, CUE- 101, were compared to the drug concentration-time profiles of a similar homodimeric TMP, CUE- 102, which is the subject of a clinical trial CUE-102-01 (NCT05360680). CUE-102 is substantially identical to CUE- 101, except that CUE- 102 has a non-HPV peptide instead of the HPV E7 peptide (YMLDLQPETT) (SEQ ID NO: 20) present in CUE-101. CUE-102 also comprises a linker disulfide, whereas CUE- 101 does not. CUE-102 does not contain a C-terminal lysine on the IgGl Fc polypeptide. The drug concentration-time profiles of TMPs CUE-101 and CUE-102 administered in weight-based doses to rats and cynomolgus monkeys, are shown in FIGS. 13 and 14, respectively. The drug concentrationtime profiles of TMPs CUE-101 and CUE-102 administered in weight-based concentrations to humans are shown in FIGS. 15A-15D. The 3 -compartment PK model for CUE-101 provided a good fit to CUE-102 data as indicated by the basic goodness of fit plot (FIG. 16), which illustrates the observed drug concentrations of CUE-101 and CUE-102 versus the individual predicted concentrations.

[0192] Preliminary analysis of CUE-102 exposure in patients demonstrates comparability to that observed with CUE-101, consistent with the preclinical experience with both molecules across multiple species. The similarity in the PK profiles of CUE-101 and CUE-102 support a conclusion that dimeric TMPs having similar polypeptide components to CUE-101 may be administered in fixed doses that substantially correspond to weight-based doses administered to human patients in amounts of from 1 mg / kg to 8 mg / kg, including weight-based dosages of from 2 mg / kg to 4 / mg / kg, which substantially correspond to fixed dosages of from about 150 mg to about 300 mg.

Claims

Attorney Docket No. 33194-0001 WOCLAIMSWhat is claimed is:

1. A sealed container comprising a fixed dose of a dimeric T cell modulatory protein (DTMP), or a plurality of sealed containers, each comprising a predetermined portion of a fixed dose of a DTMP, wherein the DTMP comprises two T cell modulatory proteins (TMPs), wherein each TMP comprises the following components: a) a first polypeptide comprising: i) a human papillomavirus epitope, wherein the epitope comprises the amino acid sequence YMLDLQPETT (SEQ ID NO:20); and ii) a first major histocompatibility complex (MHC) polypeptide, wherein the first MHC polypeptide is a p2-microglobulin (P2M) polypeptide comprising an amino acid sequence as set forth in SEQ ID NO: 17, and b) a second polypeptide comprising: i) two copies of an IL-2 polypeptide, each copy comprising an amino acid sequence set forth in SEQ ID NO:22; iii) a second MHC polypeptide, wherein the second MHC polypeptide is an MHC class I heavy chain polypeptide comprising an amino acid sequence as set forth in SEQ ID NO: 19; and iv) an immunoglobulin (Ig) Fc polypeptide, wherein the first polypeptide and the second polypeptide are covalently linked to one another via a disulfide bond, wherein the heterodimers are linked by two disulfide bonds that join the Ig Fc polypeptide of one heterodimer to the Ig Fc polypeptide of the other heterodimer, wherein the fixed dose of the DTMP is not based on the weight of any one individual patient, and optionally wherein the fixed dose of the DTMP is from 135 mg to 330 mg, from 150 to 300 mg, from 135 mg to 165mg, from 165 mg to 270 mg, or from 270 mg to 330 mg.

2. A sealed container comprising a fixed dose of a dimeric T cell modulatory protein (DTMP), or a plurality of sealed containers, each comprising a predetermined portion of a fixed dose of a DTMP,Attorney Docket No. 33194-0001 WO wherein the DTMP comprises two T cell modulatory proteins (TMPs), wherein each TMP comprises the following components: a) a first polypeptide comprising: i) a human papillomavirus epitope, wherein the epitope comprises the amino acid sequence YMLDLQPETT (SEQ ID NO:20); and ii) a first major histocompatibility complex (MHC) polypeptide, wherein the first MHC polypeptide is a p2-microglobulin (P2M) polypeptide comprising an amino acid sequence as set forth in SEQ ID NO: 17, and b) a second polypeptide comprising: i) two copies of an IL-2 polypeptide, each copy comprising an amino acid sequence set forth in SEQ ID NO:22; iii) a second MHC polypeptide, wherein the second MHC polypeptide is an MHC class I heavy chain polypeptide comprising an amino acid sequence as set forth in SEQ ID NO: 19; and iv) an immunoglobulin (Ig) Fc polypeptide, wherein the first polypeptide and the second polypeptide are covalently linked to one another via a disulfide bond, wherein the fixed dose of the DTMP is not based on the weight of any one individual patient, and wherein the fixed dose of the DTMP is 150 mg or 300 mg.

3. A method of treating cancer in a human patient in need of such treatment comprising administering to said patient a fixed dose of DTMP according to claim 1 or 2, wherein the cancer is an HPV16-positive cancer, and wherein the patient is administered a dose that is irrespective of the weight of the patient, i.e., the dose administered to the patient is not dependent on, or adjusted for, the weight of the patient.

4. The method of claim 3, wherein the cancer is a newly diagnosed HPV16+ head and neck cancer, or is a recurrent and / or metastatic HPV16+ head and neck cancer.

5. The method of claim 4, wherein the HPV16+ head and neck cancer is an oropharynx squamous cell cancer.Attorney Docket No. 33194-0001 WO6. The method of claim 4 wherein the HPV16+ head and neck cancer is an oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, or laryngeal cancer.

7. The method of claim 3, wherein the HPV16+ cancer is penile cancer.

8. The method of claim 3, wherein the HPV16+ cancer is anal cancer.

9. The method of claim 3, wherein the HPV16+ cancer is vaginal cancer.

10. The method of claim 3, wherein the HPV16+ cancer is vulvar cancer.

11. The method of claim 3, wherein the HPV16+ cancer is cervical cancer.

12. The method of any one of claims 3-11, wherein the fixed dose of DTMP is administered to an individual who (i) had no prior therapies following an initial diagnosis of HPV16+ cancer, (ii) had at least one prior therapy following an initial diagnosis of HPV16+ cancer and was determined to have progressive disease, (iii) is receiving the composition as a neoadjuvant therapy for an HPV16+ cancer, (iv) is receiving the composition as an adjuvant therapy for an HPV16+ cancer, (v) is receiving the composition as a first line treatment following a diagnosis of recurrent and / or metastatic HPV16+ cancer, (vi) is receiving the composition as a second line or beyond therapy following a diagnosis of recurrent and / or metastatic HPV16+ cancer and a diagnosis of progressive disease following the patient’s prior line of treatment, or (vii) has become refractory to a prior treatment for an HPV16+ cancer, has failed to respond to a prior treatment for an HPV16+ cancer, and / or has been determined to have progressive disease following a prior treatment for an HPV 16+ cancer, optionally wherein the determination of progressive disease is based on RECIST 1.1 criteria, iRECIST criteria, or irRECIST criteria.

13. The method of any one of claims 3-12, wherein the fixed dose of DTMP is administered as an injectable.

14. The method of claim 13, wherein the fixed dose of DTMP is administered subcutaneously, intraperitoneally, intramuscularly, or intravenously.Attorney Docket No. 33194-0001 WO15. The method of any one of claims 3-14, wherein the fixed dose of DTMP is administered every three weeks or every six weeks, and wherein the patient is receiving a therapy other than a neoadjuvant therapy.

16. The method of any one of claims 3-15, wherein the cancer is associated with a PD- L1 Combined Positive Score (PD-L1 CPS) that is from 1-19 or from 20-100.

17. The method of any one of claims 3-15, wherein the cancer is associated with a PD- L1 CPS that is either 0 or more than 0 but less than 1.

18. The method of claim 16 or 17, wherein the PD-L1 CPS is determined by an Approved Laboratory using:(i) a PD-L1 IHC 22C3 pharmDx assay or an assay that employs a monoclonal mouse anti-PD-Ll antibody, clone 22C3;(ii) a PD-L1 IHC 28-8 pharmDx assay or an assay that employs a monoclonal mouse anti-PD-Ll antibody, clone 28-8; or(iii) an assay other than (i) or (ii).

19. The method of any one of claims 3-18, further comprising administering an immune checkpoint inhibitor (CPI) to the patient, wherein the fixed dose of DTMP and checkpoint inhibitor are administered at the same time or at different times.

20. The method of claim 19, wherein the immune checkpoint inhibitor is an antibody that binds to a polypeptide chosen from CD27, CD28, CD40, CD 122, CD96, CD73, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137, ICOS, A2AR, B7-H3, B7- H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, CD122, PD-1, PD-L1, and PD-L2.

21. The method of claim 20, wherein the immune checkpoint inhibitor is an antibody specific for PD-1, PD-L1, CTLA-4, LAG3, or TIGIT,22. The method of claim 21, wherein the checkpoint inhibitor is an antibody specific for CTLA-4.

23. The method of claim 22, wherein the antibody is ipilimumab or tremelimumab.Attorney Docket No. 33194-0001 WO24. The method of claim 21, wherein the checkpoint inhibitor is an antibody specific for LAG3.

25. The method of claim 21, wherein the checkpoint inhibitor is an antibody specific for TIGIT.

26. The method of claim 20, wherein the CPI is an antibody that binds PD-1.

27. The method of claim 26, wherein the CPI is pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, or tislelizumab.

28. The method of claim 27, wherein the CPI is pembrolizumab and is administered in an amount of 200 mg every three weeks or 400 mg every six weeks.

29. The method of claim 27, wherein the CPI is nivolumab and is administered in an amount of 240 mg every 2 weeks or 480 mg every 4 weeks.

30. The method of any one of claims 26-29, wherein the CPI is administered subcutaneously, optionally wherein the CPI is pembrolizumab or nivolumab.

31. The method of claim 20, wherein the CPI is an antibody that binds PD-L1.

32. The method of claim 31, wherein the CPI is atezolizumab.

33. The method of claim 31, wherein the CPI is avelumab, or durvalumab.

34. The method of any one of claims 3-18, further comprising administering to the patient a multi-specific antibody (e.g., a bispecific antibody) or a multi-target fusion protein that binds to at least one immune checkpoint, wherein the fixed dose of DTMP and multi-specific antibody (e.g., bispecific antibody) or a multi-target fusion protein are administered at the same time or at different times.

35. The method of claim 34, wherein the multi-specific antibody (e.g., bispecific antibody) or a multi-target fusion protein binds to at least one of PD-1, PD-L1, CTLA-4, TIGIT, PVRIG and / or CD96.Attorney Docket No. 33194-0001 WO36. The method of claim 34 or 35, wherein the multi-specific antibody (e.g., bispecific antibody) or multi-target fusion protein additionally binds to non-CPI target, e.g., VEGF, VEGF-A, a VEGF receptor (e.g., VEGFR-1, VEGFR-2 or VEGFR-3), 4-1BB, or TGF-0.

37. The method of claim 36, wherein the multi-specific antibody (e.g., bispecific antibody) antibody or multi-target fusion protein binds to (i) PD-1 or PD-L1, and (ii) VEGF, VEGF- A, or VEGFRl .

38. The method of claim 36, wherein the patient is administered a bispecific antibody that binds to (i) PD-1 or PD-L1, and (ii) VEGF.

39. The method of claim 35, wherein the multi-specific (e.g., bispecific) antibody or multi-target fusion protein is BNT327, PM1009, PM1022, PM8001, PM1003, LM-299, Ivonescimab, SSGJ-707, AP505, JS207, Palverafusp alfa, RC148, Sotiburafusp alfa, AI-081, MHB039A, MK-2010, CVL006, or SGI408.

40. The method of any one of claims 3-39, further comprising the administration to said patient a plurality of cytotoxic T cells, wherein the plurality comprises CAR-T cells that comprise a receptor that binds to an HPV antigen on a cancer cell.

41. The method of any one of claims 3-39, further comprising the administration to said patient a plurality of cytotoxic T cells, wherein the plurality comprises TCR-T cells comprise a T cell receptor that binds to an HPV antigen on a cancer cell.

42. The method of claim 40 or 41, wherein the fixed dose of DTMP and the plurality of cytotoxic T cells are administered at the same time or at different times.

43. A kit compri sing :(a) a sealed container or a plurality of sealed containers according to claim 1 ; and(b) instructions for administering a fixed dose of DTMP.

44. The kit of claim 43, wherein the fixed dose of DTMP is i) from about 25 mg to about 135 mg, from about 50 mg to about 125 mg, from about 75 mg to about 100 mg, from about 135 mg to about 330 mg, from about 150 to about 300 mg, from about 135 mg to about 165 mg, from about 165 mg toAttorney Docket No. 33194-0001 WO about 270 mg, from about 270 mg to about 330 mg, from about 350 to about 400 mg, from about 450 mg to about 495 mg, or ii) from 25 mg to 135 mg, from 50 mg to 125 mg, from 75 mg to 100 mg, from 135 mg to 330 mg, from 150 to 300 mg, from 135 mg to 165 mg, from 165 mg to 270 mg, or from 270 mg to 330 mg, from 350 to 400 mg, or from 450 mg to 495 mg.

45. The kit of claim 43, wherein the fixed dose of DTMP is 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, or 330 mg.

46. The kit of claim 43, wherein the fixed dose of DTMP is about 350 mg, 350 mg, about 375 mg, 375 mg, about 400 mg, 400 mg, about 425 mg, 425 mg, about 450 mg, or 450 mg.

47. A kit for treating a patient with an HPV 16+ cancer, the kit comprising:(c) the sealed container or plurality of sealed containers (e.g. vials) according to claim 1; and(d) instructions for using the fixed dose of DTMP in the method of any one of claims 3-42.

48. The kit of claim 47, wherein the wherein the fixed dose of DTMP is 150 mg.

49. The kit of claim 47, wherein the fixed dose of DTMP is 225 mg.

50. The kit of claim 47, wherein the fixed dose of DTMP is 300 mg.

51. Use of the sealed container or a plurality of sealed containers of claim 1 or 2, or the kit of any one of claims 43-50 for treating an individual suffering from an HPV+ cancer.

52. Use of the sealed container or a plurality of sealed containers of claim 1 or 2, or the kit of any one of claims 43-50 for the preparation of a medicament for treating an individual suffering from an HPV+ cancer.Attorney Docket No. 33194-0001 WO53. The use of claim 51 or 52, wherein the HPV16+ cancer is an oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer, penile cancer, anal cancer, vaginal cancer, vulvar cancer, or cervical cancer.

54. The sealed container or plurality of sealed containers (e.g. vials) according to claim 1 or 2, wherein the DTMP is CUE-101.

55. The method of any one of claims 3-42, wherein the DTMP is CUE-101.

56. The kit according to any one of claims 43-50, wherein the DTMP is CUE-101.

57. The use according to any one of claims 51-53, wherein the DTMP is CUE-101.

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