Compositions comprising antibodies having PIGR-binding peptides and methods of use thereof

Abstract

Disclosed herein are anti-KRAS antibodies comprising a PIGR-binding peptide and methods of using the disclosed anti-KRAS antibodies to treat cancer.

Description

Polsinelli 24-3026-WO COMPOSITIONS COMPRISING ANTIBODIES HAVING PIGR-BINDING PEPTIDES AND METHODS OF USE THEREOF I. CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 708,368 filed 17 October 2024 and U.S. Provisional Application No.63 / 782,151 filed 2 April 2025, each of which is incorporated by reference herein in its entirety. II. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under Federal Grant No. CA297896 awarded by the National Cancer Institute. The Federal Government has certain rights to this invention. III. REFERENCE TO THE SEQUENCE LISTING

[0003] The Sequence Listing submitted 16 October 2025 as an XML file named “24-3026- WO_SL”, created on 16 October 2025 and having a size of 147,456 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5). IV. BACKGROUND

[0004] Despite their long half-life, therapeutic antibodies are considered ineffective against intracellular antigens due to their large size, which renders them unable to penetrate the cytoplasm. Therefore, the development of antibody-based immunotherapies has been thus far limited to transmembrane or extracellular targets. However, most oncodrivers underpinning tumor- promoting pathways are intracellular proteins inaccessible to conventional therapeutic antibodies. Considerable efforts have been made to develop small molecules that target these intracellular pathways by inhibiting enzymatic activity or serving as allosteric modulators. Small molecule inhibitors that target oncodrivers offer great therapeutic benefits and have made a big impact in oncology. However, the half-life of many small molecules is approximately 6 hours, which can limit on target interactions. In contrast, the serum half-life of optimized antibodies is > 20, which offers more sustained neutralization and can thus be less frequently dosed.

[0005] Mutant KRAS is an example of an intracellular oncodriver. Oncogenic mutations in KRAS lead to it being permanently bound by GTP (as opposed to GDP) rendering KRAS constitutively active. The mutated KRAS oncogene is found in approximately 90% of pancreatic adenocarcinomas, 40% of colorectal cancer, 30% of lung cancers, and generally in about 20-30% of all human cancers, with the G12D mutation being the most frequent at approximately 43%, representing nearly 50,000 US patients annually. These cancers are particularly difficult to treat - with a tendency to poor outcomes, due to an association between KRAS mutations and lack of response to EGFR tyrosine kinase inhibitors and chemotherapy.Polsinelli 24-3026-WO

[0006] Thus, there remains an unmet medical need for targeting mutant KRAS to enhance the efficacy of cancer therapies and cancer treatments. V. BRIEF DESCRIPTION OF THE FIGURES

[0007] FIG.1A shows the region of PIGR where IgG antibodies bind through 16-mer tail. FIG. 1B shows the homology of various PIGR binding peptides.

[0008] FIG.2 shows the binding predictions for a 12-mer binding peptide and a 16-mer binding peptide as well as the residues predicted to interact with PIGR.

[0009] FIG.3 shows the amino acids of PIGR that are predicted to bind to either the previous 16- mer or the new 12-mer. While the regions are similar, the interacting AAs appear to be different:

[0010] FIG. 4 shows that when the T3 antibody was connected to either PIGR-binding peptide, the antibody was able to abrogate the growth of established A427 tumors (when compared to the control IgG4 (i.e., 200 µg every 4 days).

[0011] FIG.5 shows that penetration into endometrial cancer cells of green fluorescently labeled modified IgG with a 12-mer PIGR-binding peptide after 50 min (overlap with bright field on the right).

[0012] FIG.6 shows that KRAS-G12D-specific antibodies (200 µg every 4 days) – with a 20-mer PIGR-binding peptide and a 16-mer PIGR-binding peptide - had an effect at delaying the progression of H23 lung tumors in vivo. The data indicate that the conformational change recognized by these Abs is conserved between KRAS G12D and KRAS G12C mutations.

[0013] FIG. 7 shows that treatments with Vaultumab connected to the original 20-mer (6 injections of 200 µg IP every 4 days) remain partially effective against established, while 20 daily IP injections of 30 mg / kg of MRTX-1133 remain as ineffective as control IgG4 or PBS. Tumor cell penetrating antibodies connected to small peptides with the capacity to bind to PIGR and trigger bona fide transcytosis prolonged KRAS inhibition after tumors had become resistant to emerging small molecule inhibitors. VI. BRIEF SUMMARY

[0014] Disclosed herein is an anti-KRAS antibody comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) binding peptides, wherein the antibody recognizes the GTP-bound active form of KRAS.

[0015] Disclosed herein is an antibody recognizing the GTP-bound active conformation of KRAS comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) binding peptides, wherein the antibody recognizes the GTP-bound active form of KRAS.

[0016] Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR-binding peptide and comprising thePolsinelli 24-3026-WO sequence set forth in SEQ ID NO:05. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:05. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL having the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH having a PIGR-binding peptide having the sequence set forth in SEQ ID NO:05. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH comprising a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:05.

[0017] Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:17, and (ii) a VH comprising a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:13. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR- binding peptide and comprising the sequence set forth in SEQ ID NO:10.

[0018] Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:06. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:18, and (ii) a VH having a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:06. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH having a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:06. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH comprising a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:06.

[0019] Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:07. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:18, and (ii) a VH having a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:07. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in any one of SEQ ID NO:21 –Polsinelli 24-3026-WO SEQ ID NO:27, and (ii) a VH having a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:07. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH comprising a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:07.

[0020] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed anti- KRAS antibody. Disclosed herein is a method for treating a subject having cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti-KRAS antibodies or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies. VII. DETAILED DESCRIPTION

[0021] The present disclosure describes formulations, compounded compositions, kits, capsules, containers, and / or methods thereof. It is to be understood that the inventive aspects of which are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0022] 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. 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 the present invention is not entitled to antedate such publication by virtue of prior invention. A. Definitions

[0023] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.Polsinelli 24-3026-WO

[0024] This disclosure describes inventive concepts with reference to specific examples. However, the intent is to cover all modifications, equivalents, and alternatives of the inventive concepts that are consistent with this disclosure.

[0025] As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0026] The phrase ‘consisting essentially of’ limits the scope of a claim to the recited components in a composition or the recited steps in a method as well as those that do not materially affect the basic and novel characteristic or characteristics of the claimed composition or claimed method. The phrase ‘consisting of’ excludes any component, step, or element that is not recited in the claim. The phrase ‘comprising’ is synonymous with ‘including’, ‘containing’, or ‘characterized by’, and is inclusive or open-ended. ‘Comprising’ does not exclude additional, unrecited components or steps.

[0027] In an aspect, when referring to any numerical value, the term ‘about’ means a value falling within a range that is ± 10% of the stated value.

[0028] Ranges can be expressed herein as from ‘about’ one particular value, and / or to ‘about’ another particular value. When such a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent ‘about,’ it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as ‘about’ that particular value in addition to the value itself. For example, if the value ‘10’ is disclosed, then ‘about 10’ is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0029] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0030] In an aspect, the terms ‘optional’ or ‘optionally’ means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. In an aspect, a disclosed method canPolsinelli 24-3026-WO optionally comprise one or more additional steps, such as, for example, repeating an administering step or altering an administering step.

[0031] In an aspect, the term ‘subject’ refers to the target of administration, e.g., a human being. The term ‘subject’ also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). Thus, the subject of the disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Alternatively, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex, and thus, adult and child subjects, as well as fetuses, whether male or female, are intended to be covered. In an aspect, a subject can be a human patient. In an aspect, a subject can have cancer, be suspected of having cancer, or be at risk of developing cancer.

[0032] In an aspect, the term ‘diagnosed’ means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof, or by one or more disclosed methods. For example, ‘diagnosed with a disease or disorder’ means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition (such as a mutant KRAS-driven cancer) that can be treated by one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof, or by one or more disclosed methods. For example, “suspected of having a disease or disorder” can mean having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition (such as a mutant KRAS-driven cancer) that can likely be treated by one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof, or by one or more disclosed methods. In an aspect, an examination can be physical, can involve various tests (e.g., blood tests, genotyping, biopsies, etc.), scans (e.g., CT scans, PET scans, etc.), and assays (e.g., enzymatic assay), or a combination thereof.

[0033] A “patient” refers to a subject afflicted with a disease or disorder (e.g., a mutant KRAS- driven cancer). In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disease or disorder such as a mutant KRAS-driven cancer. In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disease orPolsinelli 24-3026-WO disorder and is seeking treatment or receiving treatment for a disease or disorder (such as mutant KRAS-driven cancer).

[0034] In an aspect, the phrase “identified to be in need of treatment for a disease or disorder,” or the like, refers to selection of a subject based upon need for treatment of the disease or disorder. For example, a subject can be identified as having a need for treatment of a disease or disorder (e.g., a mutant KRAS-driven cancer) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the cancer. In an aspect, the identification can be performed by a person different from the person making the diagnosis. In an aspect, the administration can be performed by one who performed the diagnosis.

[0035] In an aspect, “activated” and “activation” can refer to the state of a T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with induced cytokine production and detectable effector functions. The term “activated T cells” can refer to T cells that are proliferating. Signals generated through the TCR alone may be insufficient for full activation of the T cell and one or more secondary or costimulatory signals may also be required. Thus, T cell activation comprises a primary stimulation signal through the TCR / CD3 complex and one or more secondary costimulatory signals. Costimulation can be evidenced by proliferation and / or cytokine production by T cells that have received a primary activation signal, such as stimulation through the TCR / CD3 complex.

[0036] In an aspect, “inhibit,” “inhibiting”, and “inhibition” mean to diminish or decrease an activity, level, response, condition, severity, disease, or other biological parameter. This can include, but is not limited to, the complete ablation of the activity, level, response, condition, severity, disease, or other biological parameter. This can also include, for example, a 10% inhibition or reduction in the activity, level, response, condition, severity, disease, or other biological parameter as compared to the native or control level (e.g., a subject not having received one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof). Thus, in an aspect, the inhibition or reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of reduction in between as compared to native or control levels. In an aspect, the inhibition or reduction can be 10-20%, 20-30%, 30-40%, 40-50%, 50- 60%, 60-70%, 70-80%, 80-90%, or 90-100% as compared to a native or control level (e.g., a subject not having received one or more of the disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof). In an aspect, the inhibition or reductionPolsinelli 24-3026-WO can be 0-25%, 25-50%, 50-75%, or 75-100% as compared to native or control levels. In an aspect, a native or control level can be a pre-disease or pre-disorder level (such as a pre-cancer state).

[0037] The words “treat” or “treating” or “treatment” include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder (e.g., a mutant KRAS-driven cancer); preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder (e.g., a mutant KRAS-driven cancer); and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder (e.g., a mutant KRAS-driven cancer). In an aspect, the terms cover any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the undesired physiological change, disease, pathological condition, or disorder from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the physiological change, disease, pathological condition, or disorder, i.e., arresting its development; or (iii) relieving the physiological change, disease, pathological condition, or disorder, i.e., causing regression of the disease. For example, in an aspect, treating a disease or disorder can reduce the severity of an established a disease or disorder in a subject by 1%-100% as compared to a control (such as, for example, an individual not having cancer). In an aspect, treating can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of a disease or disorder (e.g., a mutant KRAS-driven cancer). For example, treating a disease or disorder can reduce one or more symptoms of a disease or disorder in a subject by 1%- 100% as compared to a control (such as, for example, an individual not having cancer). In an aspect, treating can refer to 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% reduction of one or more symptoms of an established a disease or disorder (e.g., a mutant KRAS-driven cancer). It is understood that treatment does not necessarily refer to a cure or complete ablation or eradication of a disease or disorder. However, in an aspect, treatment can refer to a cure or complete ablation or eradication of a disease or disorder (such as a mutant KRAS-driven cancer).

[0038] In an aspect, the term “prevent” or “preventing” or “prevention” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. In an aspect, preventing a disease or disorder having chromatin deregulation and / or chromatin dysregulation is intended. The words “prevent”, “preventing”, and “prevention” also refer toPolsinelli 24-3026-WO prophylactic or preventative measures for protecting or precluding a subject (e.g., an individual) not having a given a disease or disorder (such as a mutant KRAS-driven cancer) or related complication from progressing to that complication. In an aspect, preventing metastasis is intended.

[0039] In an aspect, the terms “administering” and “administration” refer to any method of providing one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof, or by one or more disclosed methods to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, the following: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intratumoral administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intraaural administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can also include hepatic intra- arterial administration or administration through the hepatic portal vein (HPV). Administration of one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof can comprise administration directly into the CNS or the PNS. Administration can be continuous or intermittent. Administration can comprise a combination of one or more routes.

[0040] In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for the one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof to treat or prevent a disease or disorder (such as a mutant KRAS-driven cancer). In an aspect, the skilled person can also alter, change, or modify an aspect of an administering step to improve efficacy of one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof.

[0041] By “determining the amount” is meant both an absolute quantification of a particular analyte (e.g., biomarker for mutant KRAS-driven cancer, for example) or a determination of the relative abundance of a particular analyte (e.g., a mutant KRAS-driven cancer biomarker). The phrase includes both direct or indirect measurements of abundance or both.Polsinelli 24-3026-WO

[0042] In an aspect, “modifying the method” can comprise modifying or changing one or more features or aspects of one or more steps of a disclosed method. In an aspect, a method can be altered by changing the amount of the one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof administered to a subject, or by changing the frequency of administration of the one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof to a subject, by changing the duration of time that one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof is administered to a subject, or by substituting for one or more of the disclosed components and / or reagents with a similar or equivalent component and / or reagent. The same applies to all disclosed anti-KRAS antibodies, disclosed isolated nucleic acid molecules, disclosed vectors disclosed cells, disclosed pharmaceutical formulations, and any combination thereof.

[0043] In an aspect, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. In an aspect, a pharmaceutical carrier employed can be a solid, liquid, or gas. In an aspect, examples of solid carriers can include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. In an aspect, examples of liquid carriers can include sugar syrup, peanut oil, olive oil, and water. In an aspect, examples of gaseous carriers can include carbon dioxide and nitrogen. In preparing a disclosed composition for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques. Proper fluidity can be maintained, for example, by the use ofPolsinelli 24-3026-WO coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0044] In an aspect, the term “excipient” refers to an inert substance which is commonly used as a diluent, vehicle, preservative, binder, or stabilizing agent, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants (e.g., SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g., sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol, sorbitol, etc.). See, also, for reference, Remington’s Pharmaceutical Sciences, (1990) Mack Publishing Co., Easton, Pa., which is hereby incorporated by reference in its entirety.

[0045] In an aspect, “concurrently” means (1) simultaneously in time, or (2) at different times during the course of a common treatment schedule.

[0046] In an aspect, the term “contacting” refers to bringing one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, the disclosed anti-chemokines, the disclosed anti- cancer agents, the disclosed chemotherapeutics, or any combination thereof together with a target area or intended target area in such a manner that the disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosedPolsinelli 24-3026-WO pharmaceutical formulations, the disclosed anti-chemokines, the disclosed anti-cancer agents, the disclosed chemotherapeutics, or any combination thereof can exert an effect on the intended target or targeted area either directly or indirectly. A target area or intended target area can be one or more of a subject’s organs (e.g., lungs, heart, liver, kidney, brain, etc.) hosting cancerous cells. In an aspect, a target area or intended target area can be any cell or any organ infected by a disease or disorder (such as a mutant KRAS-driven cancer). In an aspect, a target area or intended target area can be any organ, tissue, or cells that are affected by a disease or disorder (such as a mutant KRAS-driven cancer). In an aspect, a target or intended target can be a blood-borne cancer or a hematologic cancer.

[0047] In an aspect, “determining” can refer to measuring or ascertaining the presence and severity of a disease or disorder, such as, for example, a hematologic cancer. Methods and techniques used to determine the presence and / or severity of a disease or disorder are typically known to the medical arts. For example, the art is familiar with the ways to identify and / or diagnose the presence, severity, or both of a disease or disorder (such as, for example, cancer).

[0048] In an aspect, “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired result such as, for example, the treatment and / or prevention of a disease or disorder (e.g., a mutant KRAS-driven cancer) or a suspected disease or disorder (e.g., a mutant KRAS-driven cancer). In an aspect, the terms “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired an effect on an undesired condition (e.g., a mutant KRAS-driven cancer). For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. In an aspect, “therapeutically effective amount” means an amount of one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, the disclosed anti-chemokines, the disclosed anti- cancer agents, the disclosed chemotherapeutics, or any combination thereof that (i) treats the particular disease, condition, or disorder (e.g., a mutant KRAS-driven cancer), (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder e.g., a mutant KRAS-driven cancer), or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein (e.g., a mutant KRAS-driven cancer). The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or any combination thereofPolsinelli 24-3026-WO employed; the disclosed methods employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or any combination thereof employed; the duration of the treatment; drugs used in combination or coincidental with the one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or any combination thereof employed, and other like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, the disclosed anti- chemokines, the disclosed anti-cancer agents, the disclosed chemotherapeutics, or any combination thereof at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, then the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, a single dose of the disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, the disclosed anti-chemokines, the disclosed anti-cancer agents, the disclosed chemotherapeutics, or any combination thereof can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition, such as, for example, a mutant KRAS-driven cancer.

[0049] The term “antibody” (Ab) includes, without limitation, a glycoprotein immunoglobulin that binds specifically to an antigen. An antibody can comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof. Each H chain can comprise a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region can comprise three constant domains, CH1, CH2 and CH3. Each light chain can comprise a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region can comprise one constant domain, CL. The VH and VL regions can be further subdivided into regions ofPolsinelli 24-3026-WO hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL can comprise three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains can contain a binding peptide that interacts with an antigen. The constant regions of the Abs can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Generally, human antibodies can be approximately 150 kD tetrameric agents composed of two identical heavy (H) chain polypeptides (about 50 kD each) and two identical light (L) chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a “Y-shaped” structure. The heavy and light chains can be linked or connected to one another by a single disulfide bond and two other disulfide bonds can connect the heavy chain hinge regions to one another, so that the dimers can be connected to one another and the tetramer can be formed. Naturally produced antibodies are also glycosylated, e.g., on the CH2domain. The term “antibody” is used to mean an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing etc., through at least one antigen recognition site within the variable region of the immunoglobulin molecule. In an aspect, the term encompasses intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab′, F(ab′)2, and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies such as bispecific antibodies generated from at least two intact antibodies, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity. An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.

[0050] In an aspect, “variable region” or “variable domain” are used interchangeably. The variable region typically refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The variability in sequence is concentrated in those regions called complementarityPolsinelli 24-3026-WO determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). It is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with antigen. In an aspect, the variable region can be a human variable region. In an aspect, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In an aspect, the variable region is a primate (e.g., non-human primate) variable region. In an aspect, the variable region comprises rodent or murine CDRs and primate framework regions (FRs).

[0051] The terms “VL” and “VL domain” are used interchangeably to refer to the light chain variable region of an antibody or an antigen-binding molecule thereof. The terms “VH” and “VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody or an antigen-binding molecule thereof.

[0052] In an aspect, “conjugate” or “conjugated” can be used to define the operative association of one disclosed component to another disclosed component. In an aspect, conjugated does not intend to refer solely to any type of operative association and is not particularly limited to chemical “conjugation”.

[0053] As known to the skilled person, IgG can bind to cell surface receptors on many types of cells to bring about an assortment of effects, for example, (i) the enabling of phagocytosis (e.g., monocytes, macrophages, neutrophils), (ii) antibody-dependent cellular cytotoxicity (monocytes, macrophages and lymphocytes), or (iii) to effect feedback control on antibody synthesis (B and T lymphocytes). In an aspect, the properties of the IgG subclasses can vary, and in most cases the Fc fragments can have the same property as the intact IgG; meaning that it does not appear to be modulated by the hinge or the Fab. In an aspect, cellular Fc receptors can be classified into three categories according to structure and affinity. All the sites on IgG that can interact with these separate receptors appear to be located in the Fc region, and, in the case of the FcγRI (which is the highest affinity receptor class), the site involves residues 233–237, at the N-terminal end of the Cγ2 domain close to the hinge region but coded in the Cγ2 exon.

[0054] “Endogenous” with reference to a gene, protein, and / or nucleic acid refers to the natural presence of that gene, protein, and / or nucleic acid in a cell, such as an immune cell.

[0055] “Exogenous” refers to an introduced agent, such as a nucleic acid, gene, or protein, into a cell, for example from an outside source. A nucleic acid introduced into a cell is exogenous even if it encodes a protein which is naturally found in the cell. Such exogenous introduction of a nucleic acid encoding a protein can be used to increase the expression of the protein over the level that would naturally be found in the cell under similar conditions, e.g., without introduction of the exogenous nucleic acid.Polsinelli 24-3026-WO

[0056] In an aspect, “effector function” can refer to a biological result of interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions comprise, without limitation, antibody- dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement mediated cytotoxicity (CMC). An effector function may be antigen binding dependent, antigen binding independent, or both. ADCC refers to lysis of antibody-bound target cells by immune effector cells. ADCC is generally understood to involve Fc receptor (FcR)- bearing effector cells recognizing and subsequently killing antibody-coated target cells (e.g., cells that express on their surface antigens to which an antibody is bound). Effector cells that mediate ADCC may comprise immune cells, comprising yet not limited to, one or more of natural killer (NK) cells, macrophages, neutrophils, eosinophils.

[0057] The term “immunotherapy” refers to the treatment of a subject afflicted with, or at risk of contracting or suffering a recurrence of, a disease by a method comprising inducing, enhancing, suppressing or otherwise modifying an immune response. Examples of immunotherapy can include, but are not limited to, NK cells and T cell therapies, NK CAR T-cell and CAR T-cells therapies, and vaccines. T cell therapy can include adoptive T cell therapy, tumor-infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACTTM), and allogeneic T cell transplantation. However, one of skill in the art would recognize that the conditioning methods disclosed herein would enhance the effectiveness of any transplanted T cell therapy. The T cells or NK cells of the immunotherapy can come from any source known in the art. For example, T cells and NK cells can be differentiated in vitro from a hematopoietic stem cell population (for example iPSCs) or can be obtained from a subject. T cells and NK cells can be obtained from, e.g., peripheral blood mononuclear cells (PBMCs), bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In addition, the T cells can be derived from one or more T cell lines available in the art. T cells can also be obtained from a unit of blood collected from a subject using techniques known to the skilled person.

[0058] In an aspect, the term “humanized antibody” refers to forms of non-human (e.g., murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human sequences. Typically, humanized antibodies are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, hamster, etc.) that have the desired specificity, affinity, and capability. In some instances, the Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody from a non-human species that has the desired specificity, affinity, and capability. ThePolsinelli 24-3026-WO humanized antibody can be further modified by the substitution of additional residue either in the Fv framework region and / or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and / or capability. In general, the humanized antibody will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin.

[0059] That an antibody “selectively binds” or “specifically binds” to an epitope or receptor means that the antibody reacts or associates more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to the epitope or receptor than with alternative substances, including unrelated proteins. “Selectively binds” or “specifically binds” means, for instance, that an antibody binds to a protein with a KD of about 0.1 mM or less, more usually about 1 μM or less. “Selectively binds” or “specifically binds” means at times that an antibody binds to a protein with a KD of about 0.1 mM or less, at times about 1 μM or less, at times about 0.1 μM or less, at times about 0.01 μM or less, and at times about 1 nM or less. It is understood that, in an aspect, an antibody or binding moiety that specifically binds to a first target may or may not specifically bind to a second target. As such, “specific binding” does not necessarily require (although it can include) exclusive binding, e.g., binding to a single target.

[0060] A “target” or “target antigen” is any molecule bound by a binding motif (e.g., a PIGR- expressing cancer cell). A disclosed target can be cells and / or tissues in a subject.

[0061] In an aspect, PIGR or polymeric immunoglobulin receptor plays a unique role in the mucosal immune system, acting both as an epithelial transporter and as an integral component of secretory immunoglobulins. The human pIgR gene (NCBI gene ID: 5284) is located on the q32.1 region of chromosome 1. With a total of 11 exons, the human pIgR gene spans about 19 kb.

[0062] “Antigen-specific targeting region” (ASTR) refers to the region of a disclosed anti-KRAS antibody that targets specific antigens. In an aspect, the antigen-specific targeting regions comprise an antibody or a functional equivalent thereof or a fragment thereof or a derivative thereof and each of the targeting regions target a different antigen. The targeting regions may comprise full length heavy chain, Fab fragments, single chain Fv (scFv) fragments, divalent single chain antibodies or diabodies, each of which are specific to the target antigen.

[0063] In an aspect, the terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, andPolsinelli 24-3026-WO leukemia. More particular examples of such cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer.

[0064] The terms “proliferative disorder” and “proliferative disease” refer to disorders associated with abnormal cell proliferation such as cancer.

[0065] In an aspect, “tumor” and “neoplasm” refer to any mass of tissue that result from excessive cell growth or proliferation, either benign (noncancerous) or malignant (cancerous) including pre- cancerous lesions.

[0066] In an aspect, “metastasis refers to the process by which a cancer spreads or transfers from the site of origin to other regions of the body with the development of a similar cancerous lesion at the new location. A “metastatic” or “metastasizing” cell is one that loses adhesive contacts with neighboring cells and migrates via the bloodstream or lymph from the primary site of disease to invade neighboring body structures.

[0067] The terms “cancer stem cell” or “tumor stem cell” or “solid tumor stem cell” are used interchangeably herein and refer to a population of cells from a solid tumor that: (1) have extensive proliferative capacity; (2) are capable of asymmetric cell division to generate one or more kinds of differentiated progeny with reduced proliferative or developmental potential; and (3) are capable of symmetric cell divisions for self-renewal or self-maintenance. These properties of “cancer stem cells” or “tumor stem cells” or “solid tumor stem cells” confer on those cancer stem cells the ability to form palpable tumors upon serial transplantation into an immunocompromised mouse compared to the majority of tumor cells that fail to form tumors. Cancer stem cells undergo self-renewal versus differentiation in a chaotic manner to form tumors with abnormal cell types that can change over time as mutations occur.

[0068] The terms “cancer cell” or “tumor cell” and grammatical equivalents refer to the total population of cells derived from a tumor including both non-tumorigenic cells, which comprise the bulk of the tumor cell population, and tumorigenic stem cells (cancer stem cells).

[0069] In an aspect, “delay” in the context of tumor growth refers to a prolongation of the time it takes for a tumor to reach a determined size or stage as a result of, for example, a disclosed therapeutic treatment.Polsinelli 24-3026-WO

[0070] In an aspect, “abrogate” in the context of tumor growth refers to the suppression or elimination of tumor development as a result of, for example, a disclosed therapeutic treatment.

[0071] In an aspect, “tumorigenic” refers to the functional features of a solid tumor stem cell including the properties of self-renewal (giving rise to additional tumorigenic cancer stem cells) and proliferation to generate all other tumor cells (giving rise to differentiated and thus non- tumorigenic tumor cells) that allow solid tumor stem cells to form a tumor. In an aspect, the “tumorigenicity” of a tumor refers to the ability of a random sample of cells from the tumor to form palpable tumors upon serial transplantation into immunocompromised mice.

[0072] In an aspect, “lipid nanoparticles” or “LNPs” can deliver nucleic acid (e.g., DNA or RNA), protein (e.g., RNA-guided DNA binding agent), or nucleic acid together with protein. LNPs can comprise biodegradable, ionizable lipids. For example, LNPs can comprise (9Z,12Z)-3-((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-dienoate, also called 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z,12Z)-octadeca-9,12-dienoate) or another ionizable lipid. In an aspect, the term cationic and ionizable in the context of LNP lipids can be used interchangeably, e.g., wherein ionizable lipids are cationic depending on the pH.

[0073] “Sequence identity” and “sequence similarity” can be determined by alignment of two peptide or two nucleotide sequences using global or local alignment algorithms. Sequences may then be referred to as “substantially identical” or “essentially similar” when they are optimally aligned. For example, sequence similarity or identity can be determined by searching against databases such as FASTA, BLAST, etc., but hits should be retrieved and aligned pairwise to compare sequence identity. Two proteins or two protein domains, or two nucleic acid sequences can have “substantial sequence identity” if the percentage sequence identity is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more, preferably 90%, 95%, 98%, 99% or more. Such sequences are also referred to as “variants” herein, e.g., other variants of a missing, deficient, and / or mutant protein or enzyme. It should be understood that sequence with substantial sequence identity do not necessarily have the same length and may differ in length. For example, sequences that have the same nucleotide sequence but of which one has additional nucleotides on the 3”- and / or 5”-side are 100% identical.

[0074] In an aspect, “immune-modulating” refers to the ability of the one or more disclosed anti- KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof to alter (modulate) one or more aspects of the immune system. The immune system functions to protect the organism from infection and from foreign antigens by cellular and humoral mechanismsPolsinelli 24-3026-WO involving lymphocytes, macrophages, and other antigen-presenting cells that regulate each other by means of multiple cell-cell interactions and by elaborating soluble factors, including lymphokines and antibodies, that have autocrine, paracrine, and endocrine effects on immune cells.

[0075] In an aspect, “immune modulator” refers to an agent that is capable of adjusting a given immune response to a desired level (e.g., as in immunopotentiation, immunosuppression, or induction of immunologic tolerance). Examples of immune modulators include but are not limited to, a disclosed immune modulator can comprise aspirin, azathioprine, belimumab, betamethasone dipropionate, betamethasone valerate, bortezomib, bredinin, cyazathioprine, cyclophosphamide, cyclosporine, deoxyspergualin, didemnin B, fluocinolone acetonide, folinic acid, ibuprofen, IL6 inhibitors (such as sarilumab) indomethacin, inebilizumab, intravenous gamma globulin (IVIG), methotrexate, methylprednisolone, mycophenolate mofetil, naproxen, prednisolone, prednisone, prednisolone indomethacin, rapamycin, rituximab, sirolimus, sulindac, synthetic vaccine particles containing rapamycin (SVP-Rapamycin or ImmTOR), thalidomide, tocilizumab, tolmetin, triamcinolone acetonide, anti-CD3 antibodies, anti-CD4 antibodies, anti-CD19 antibodies, anti- CD20 antibodies, anti-CD22 antibodies, anti-CD40 antibodies, anti-FcRN antibodies, anti-IL6 antibodies, anti-IGF1R antibodies, an IL2 mutein, a BTK inhibitor, or a combination thereof. In an aspect, a disclosed immune modulator can comprise one or more Treg (regulatory T cells) infusions (e.g., antigen specific Treg cells to AAV). In an aspect, a disclosed immune modulator can be bortezomib or SVP-Rapamycin. In an aspect, an immune modulator can be administered by any suitable route of administration including, but not limited to, in utero, intra-CSF, intrathecally, intravenously, subcutaneously, transdermally, intradermally, intramuscularly, orally, transcutaneously, intraperitoneally (IP), or intravaginally. In an aspect, a disclosed immune modulator can be administered using a combination of routes. Administration can also include hepatic intra-arterial administration or administration through the hepatic portal vein (HPV). Administration of an immune modulator can be continuous or intermittent, and administration can comprise a combination of one or more routes.

[0076] In an aspect, the term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0077] In an aspect, the term “in combination” in the context of the administration of other therapies (e.g., other agents) includes the use of more than one therapy (e.g., drug therapy). Administration “in combination with” one or more further therapeutic agents includes simultaneous (e.g., concurrent) and consecutive administration in any order. The use of the termPolsinelli 24-3026-WO “in combination” does not restrict the order in which therapies are administered to a subject. By way of non-limiting example, a first therapy (e.g., one or more disclosed anti-KRAS antibodies, the disclosed isolated nucleic acid molecules, the disclosed vectors, the disclosed cells, the disclosed pharmaceutical formulations, or a combination thereof) can be administered prior to (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks), concurrently, or after (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks or longer) the administration of a second therapy to a subject having or diagnosed with mutant KRAS-driven cancer.

[0078] Disclosed are the components to be used to prepare the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations as well as the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific claimed compositions and / or claimed methods. B. KRAS Mutation-Driven CancersPolsinelli 24-3026-WO

[0079] The KRAS gene is a member of the rat sarcoma viral oncogene family (RAS), which includes two other isoforms in humans: the Harvey and neuroblastoma rat sarcoma viral oncogenes (HRAS, NRAS). In 1982, Weinberg and Barbacid isolated a gene from human bladder cancer cell lines. Subsequently, this gene was identified as a human homologue of the RAS gene, named HRAS, located on the short arm of chromosome 11 (11p15.1–11p15.3). In the same year, another homologue was found in human lung cancer cells, called KRAS, located on the short arm of chromosome 12 (12p11.1–12p12.1). The last gene, called NRAS, is found in human neuroblastoma and is located on the short arm of chromosome 1 (1p22–1p32).

[0080] RAS genes are evolutionarily conserved with similar structures and are composed of four exons distributed on the full length of approximately 30 kb DNA. The KRAS gene (Gene ID No. 3845; see also SEQ ID NO:16 and NG_007524.2) encodes two highly related protein isoforms, KRAS-4B (NP_001356716.1 and NM_001369787) and KRAS-4A (NP_001356715.1 and NM_001369786.1), which consist of 188 and 189 amino acids, respectively, due to different clipping of the fourth exon. The other two RAS proteins all contain 189 amino acids.

[0081] The term KRAS is generally referred to as KRAS-4B due to the high level of mRNA encoding KRAS-4B in cells. The crystal structure of RAS reveals six beta strands and five alpha helices. which form two major domains: a catalytic domain called the G domain and a hypervariable region (HVR). The G domain consists of three regions: switch I, switch II, and the P loop, which binds guanine nucleotides and activates signaling by interacting with effectors. The HVR comprises the CAAX motif related to membrane localization. From the perspective of function, RAS is a kind of membrane-bound regulatory protein (G protein) binding guanine nucleotide belonging to the family of guanosine triphosphatases (GTPases). RAS functions as a guanosine diphosphate (GDP) / triphosphate (GTP) binary switch, which controls important signal transduction from activated membrane receptors to intracellular molecules. The binary switch is mainly determined by two kinds of regulatory proteins: guanine nucleotide exchange factors (GEFs) such as son of sevenless (SOS) and GTPase-activating proteins (GAPs) such as neurofibromin 1 (NF1). In the resting state, KRAS normally binds with GDP in an inactivated state due to the intrinsic GTPase activity of KRAS, which is able to hydrolyse GTP to GDP. When the cells receive the relevant stimuli, such as the interaction of EGF and EGFR, the KRAS-GDP complex appears to have a decreased affinity of KRAS with GDP in the presence of GEFs, and then GDP is replaced by GTP, which has a higher affinity and an approximately 10-fold higher cellular concentration than GDP. KRAS-GTP binding acquires an altered conformation in switches I and II of the G domain, and then KRAS is activated and binds to its downstream molecules as a monomer or dimer to mediate a series of signaling cascades. In contrast, GAPsPolsinelli 24-3026-WO promote the binding between GDP and KRAS by enhancing the GTPase activity of KRAS, thus maintaining the inactive state of KRAS.

[0082] KRAS mutations are common in a variety of cancers. For example, a disclosed mutant KRAS can comprise KRASG12A, KRASG12C, KRASG12D, KRASG12R, KRASG12S, KRASG12V, KRASG12X, KRASG13C, KRASG13D, KRASG13X, KRASQ61H, KRASQ61L, KRASQ61K, KRASQ61R, KRASQ61X, KRASA146T, KRASA146V, KRASA146X, or any combination thereof.

[0083] KRAS mutations have been identified in about 45% of CRC cases in the United States and about 49% of CRC cases in China; about 90% of pancreatic ductal adenocarcinoma (PDAC) in the United States, and abou t89% in China; and about 35% of lung adenocarcinomas (LUAD, a subtype of non-small-cell lung cancer) in the United States, and about 13% in China. KRAS has two isomers, KRAS4A and KRAS4B, that are generated by selective splicing of the KRAS gene. The mutant subtypes of KRAS are mainly classified as KRAS (G12D), KRAS (G12V), KRAS (G12C), KRAS (G13D), KRAS (G12R), and KRAS (G12A) mutations or KRAS wild-type amplification. The distribution of KRAS mutations varies in different human cancers, with KRAS (G12C) mutation in 41% of LUAD, whereas KRAS (G12D) and KRAS (G12V) are the two most common alleles in CRC and PDAC. Notably, other KRAS alleles such as G12R are limited in PDAC. Indeed, although the tumor type is driven by KRAS mutations, its codons and the frequency of mutations vary by tissue. Genetic alteration of G12 or G13 destroys the stability of the arginine residue hydrolysis transition state. C. Compositions 1. PIGR-Binding Peptides

[0084] Disclosed herein are PIGR-binding peptides. In an aspect, a disclosed PIGR-binding peptide can be a 20-mer peptide, a 16-mer peptide, or a 12-mer peptide. In an aspect, a disclosed PIGR-binding peptide can comprise the sequence set forth in SEQ ID NO:42, SEQ ID NO:43, or SEQ ID NO:44. In an aspect, a disclosed 20-mer PIGR-binding peptide can comprise the sequence set forth in SEQ ID NO:42. In an aspect, a disclosed 16-mer PIGR-binding peptide can comprise the sequence set forth in SEQ ID NO:43. In an aspect, a disclosed 12-mer PIGR-binding peptide can comprise the sequence set forth in SEQ ID NO:44. In an aspect, a disclosed 12-mer PIGR- binding peptide can comprise the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers).

[0085] In an aspect, a disclosed PIGR-binding peptide can be a 20-mer peptide, a 16-mer peptide, or a 12-mer peptide and can comprise a linker such as, for example, a GS4 linker. In an aspect, a disclosed GS4 linker can comprise the sequence of SEQ ID NO:142 (GGGGS). In an aspect, a disclosed 20-mer PIGR-binding peptide with a GS4 linker can comprise the sequence set forth inPolsinelli 24-3026-WO SEQ ID NO:39. In an aspect, a disclosed 16-mer PIGR-binding peptide with a GS4 linker can comprise the sequence set forth in SEQ ID NO:40. In an aspect, a disclosed 12-mer PIGR-binding peptide with a GS4 linker can comprise the sequence set forth in SEQ ID NO:41.

[0086] In an aspect, a disclosed PIGR-binding peptide can comprise any binding peptide that can bind to the extracellular domain of PIGR and allows for and / or facilitates internalization of an antibody into the cell. In an aspect, a disclosed PIGR-binding peptide can comprise any binding peptide that can bind to the extracellular domain of PIGR and allows for and / or facilitates internalization of an antibody into the cell and the targeting of an intracellular antigen or antigenic target. In an aspect, a disclosed PIGR-binding peptide can reduce the antigenicity of the bound antibody. In an aspect, a disclosed PIGR-binding peptide can serve to re-direct the bound antibody to the cytosol of a PIGR+cell.

[0087] In an aspect, a disclosed antibody bound to a disclosed PIGR-binding peptide comprising the sequence of SEQ ID NO:44 can be less immunogenic than the same disclosed antibody bound to a disclosed PIGR-binding peptide comprising the sequence of SEQ ID NO:43. In an aspect, a disclosed antibody bound to a disclosed PIGR-binding peptide comprising the sequence of SEQ ID NO:44 can be less immunogenic than the same disclosed antibody bound to a disclosed PIGR- binding peptide comprising the sequence of SEQ ID NO:42. In an aspect, a disclosed antibody bound to a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be less immunogenic than the same disclosed antibody bound to a disclosed PIGR-binding peptide comprising the sequence of SEQ ID NO:42.

[0088] In an aspect, a disclosed antibody bound to a disclosed PIGR-binding peptide (with a linker) comprising the sequence of SEQ ID NO:44 can be less immunogenic than the same disclosed antibody bound to a disclosed PIGR-binding peptide (with a linker) comprising the sequence of SEQ ID NO:40. In an aspect, a disclosed antibody bound to a disclosed PIGR-binding peptide (with a linker) comprising the sequence of SEQ ID NO:44 can be less immunogenic than the same disclosed antibody bound to a disclosed PIGR-binding peptide comprising the sequence of SEQ ID NO:39.

[0089] In an aspect, a disclosed 12-mer PIGR-binding peptide can be less immunogenic than a disclosed 16-mer PIGR-binding peptide or a disclosed 20-mer PIGR-binding peptide. In an aspect, a disclosed 12-mer PIGR-binding peptide with a GS4-linker can be less immunogenic than a disclosed 16-mer PIGR-binding peptide with a GS4-linker or a disclosed 20-mer PIGR-binding peptide with a GS4-linker. In an aspect, a PIGR-binding peptide having the sequence set forth in SEQ ID NO:44 is less immunogenic than a PIGR-binding peptide having the sequence set forth inPolsinelli 24-3026-WO SEQ ID NO:43 or SEQ ID NO:42. In an aspect, a PIGR-binding peptide having the sequence set forth in SEQ ID NO:41 is less immunogenic than a PIGR-binding peptide having the sequence set forth in SEQ ID NO:40 or SEQ ID NO:39.

[0090] In an aspect, a disclosed 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) is less immunogenic than a PIGR-binding peptide having the sequence set forth in SEQ ID NO:43 or SEQ ID NO:42. In an aspect, a disclosed 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) is less immunogenic than a PIGR- binding peptide having the sequence set forth in SEQ ID NO:40 or SEQ ID NO:39. TABLE 1 – Exemplary PIGR-Binding Peptides

[0091] In an aspect, a disclosed PIGR-binding peptide can comprise the sequence set forth in any one of SEQ ID NO:125 – SEQ ID NO:141. In an aspect, a disclosed PIGR-binding peptide can comprise the sequence set forth in any one of SEQ ID NO:125 – SEQ ID NO:141 with a disclosed GS4 linker having the sequence set forth in SEQ ID NO:142. In an aspect, a disclosed PIGR can comprise the PIGR in one or more of the following sequences: HKK06575.1 (SEQ ID NO:125), MBI5842490.1 (SEQ ID NO:126), MCU6550953.1 (SEQ ID NO:127), MEZ0257417.1 (SEQ ID NO:128), PVH48350.1 (SEQ ID NO:129), RJO73794.1 (SEQ ID NO:130), RZF40058.1 (SEQ ID NO:131), VVB54476.1 (SEQ ID NO:132), WP_067705041.1 (SEQ ID NO:133),Polsinelli 24-3026-WO WP_089304588.1 (SEQ ID NO:134), WP_167474838.1 (SEQ ID NO:135), WP_225730055.1 (SEQ ID NO:136), WP_239003878.1 (SEQ ID NO:137), WP_280561738.1 (SEQ ID NO:138), XP_002982236.1 (SEQ ID NO:139), XP_039288999.1 (SEQ ID NO:140), or XP_042433022.1 (SEQ ID NO:141). These sequence identifiers represent the PIGR sequence associated with these accession numbers.

[0092] In an aspect, a disclosed 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:42 can be encoded by a sequence set forth in SEQ ID NO:48. In an aspect, a disclosed 20-mer PIGR-binding peptide with a GS4 linker comprising the sequence set forth in SEQ ID NO:39 can be encoded by a sequence set forth in SEQ ID NO:45. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 can be encoded by a sequence set forth in SEQ ID NO:49. In an aspect, a disclosed 16-mer PIGR-binding peptide with a GS4 linker comprising the sequence set forth in SEQ ID NO:40 can be encoded by a sequence set forth in SEQ ID NO:46. In an aspect, a disclosed 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 can be encoded by a sequence set forth in SEQ ID NO:50. In an aspect, a disclosed 12-mer PIGR-binding peptide with a GS4 linker comprising the sequence set forth in SEQ ID NO:41 can be encoded by a sequence set forth in SEQ ID NO:47. In an aspect, a disclosed 12-mer PIGR-binding peptide with a GS4 linker and a GS4 spacer comprising the sequence set forth in SEQ ID NO:143 can be encoded by a sequence set forth in SEQ ID NO:144.

[0093] In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that targets KRAS or a KRAS mutant (as disclosed herein and including mutant KRAS comprises KRASG12A, KRASG12C, KRASG12D, KRASG12R, KRASG12S, KRASG12V, KRASG12X, KRASG13C, KRASG13D, KRASG13X, KRASQ61H, KRASQ61L, KRASQ61K, KRASQ61R, KRASQ61X, KRASA146T, KRASA146V, KRASA146X, or any combination thereof). In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target Myd88. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target IL-22. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target TNF-α. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target cNF-kB. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target Sting. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target NLRP3. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target TNF-α. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target IL-1α. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target IL-1β. In an aspect, a disclosed PIGR-Polsinelli 24-3026-WO binding peptide can be added to a VH of an antibody that can target IL-6. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target IL-7.In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target IL-1b. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target IL- 11. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target IL-33. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target Transglutaminase 2. In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that can target cNF-kB.

[0094] In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to PIK3CAH1047Rassociated with cancer (including breast cancer). In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to PIK3CAH1047Rcan be used in a method to treat a subject having cancer (including breast cancer). In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR- binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to PIK3CAE545Kassociated with cancer including breast cancer, prostate cancer, cervical cancer, non-small cell lung cancer, or colorectal cancer. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to PIK3CAE545Kcan be used in a method to treat a subject having cancer including breast cancer, prostate cancer, cervical cancer, non-small cell lung cancer, or colorectal cancer).

[0095] In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to BRAFVV600Eassociated with cancer. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to BRAFVV600Ecan be used in a method to treat a subject having cancer.

[0096] In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to BRAFV600Eassociated with cancer. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to BRAFVV600Ecan be used in a method to treat a subject having cancer.

[0097] In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to TP53R248Qassociated with cancer including prostate cancer, bladder cancer, pancreatic cancer, head and neck cancer, esophageal cancer, endometrial cancer, stomach cancer, cervical cancer, or any combination thereof. In an aspect, a disclosed PIGR- binding peptide provided in Table 1 linked to an antibody that recognizes and binds to TP53R248QPolsinelli 24-3026-WO can be used in a method to treat a subject having prostate cancer, bladder cancer, pancreatic cancer, head and neck cancer, esophageal cancer, endometrial cancer, stomach cancer, cervical cancer, or any combination thereof.

[0098] In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to TP53R273Hassociated with cancer including breast cancer, colon cancer, head and neck cancer, ovarian cancer, or any combination thereof. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to TP53R273Hcan be used in a method to treat a subject having breast cancer, colon cancer, head and neck cancer, ovarian cancer, or any combination thereof.

[0099] In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to NRASQ61Kassociated with cancer. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to NRASQ61Kcan be used in a method to treat a subject having cancer.

[0100] In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that targets KRAS or a KRAS mutant (as disclosed herein). In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target Myd88. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target IL-22. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target TNF-α. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target cNF-kB. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibodyPolsinelli 24-3026-WO that can target Sting. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target NLRP3. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target TNF-α. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target IL-1α. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target IL-1β. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target IL-6. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target IL-7.In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target IL-1b. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target IL-11. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target IL-33. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target Transglutaminase 2. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target cNF-kB.

[0101] In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 can be linked to an antibody that recognizes and binds to PIK3CAH1047Rassociated with cancer (including breast cancer). In an aspect, a disclosed PIGR-Polsinelli 24-3026-WO binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 linked to an antibody that recognizes and binds to PIK3CAH1047Rcan be used in a method to treat a subject having cancer (including breast cancer). In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 can be linked to an antibody that recognizes and binds to PIK3CAE545Kassociated with cancer including breast cancer, prostate cancer, cervical cancer, non-small cell lung cancer, or colorectal cancer. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 linked to an antibody that recognizes and binds to PIK3CAE545Kcan be used in a method to treat a subject having cancer including breast cancer, prostate cancer, cervical cancer, non-small cell lung cancer, or colorectal cancer).

[0102] In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 can be linked to an antibody that recognizes and binds to BRAFVV600Eassociated with cancer. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 linked to an antibody that recognizes and binds to BRAFVV600Ecan be used in a method to treat a subject having cancer.

[0103] In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 can be linked to an antibody that recognizes and binds to BRAFV600Eassociated with cancer. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 linked to an antibody that recognizes and binds to BRAFVV600Ecan be used in a method to treat a subject having cancer.Polsinelli 24-3026-WO

[0104] In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 can be linked to an antibody that recognizes and binds to TP53R248Qassociated with cancer including prostate cancer, bladder cancer, pancreatic cancer, head and neck cancer, esophageal cancer, endometrial cancer, stomach cancer, cervical cancer, or any combination thereof. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 linked to an antibody that recognizes and binds to TP53R248Qcan be used in a method to treat a subject having prostate cancer, bladder cancer, pancreatic cancer, head and neck cancer, esophageal cancer, endometrial cancer, stomach cancer, cervical cancer, or any combination thereof.

[0105] In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 can be linked to an antibody that recognizes and binds to TP53R273Hassociated with cancer including breast cancer, colon cancer, head and neck cancer, ovarian cancer, or any combination thereof. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 linked to an antibody that recognizes and binds to TP53R273Hcan be used in a method to treat a subject having breast cancer, colon cancer, head and neck cancer, ovarian cancer, or any combination thereof.

[0106] In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 can be linked to an antibody that recognizes and binds to NRASQ61Kassociated with cancer. In an aspect, a disclosed PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) provided in Table 1 linked to an antibody that recognizes and binds to NRASQ61Kcan be used in a method to treat a subject having cancer.

[0107] In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that targets KRAS or a KRAS mutant (as disclosed herein and including mutant KRAS comprises KRASG12A, KRASG12C, KRASG12D, KRASG12R, KRASG12S, KRASG12V, KRASG12X, KRASG13C, KRASG13D, KRASG13X, KRASQ61H, KRASQ61L, KRASQ61K, KRASQ61R, KRASQ61X, KRASA146T, KRASA146V, KRASA146X, or any combination thereof). In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibodyPolsinelli 24-3026-WO that can target Myd88. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target IL-22. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 comprising the sequence set forth in SEQ ID NO:44 (no GS4), SEQ ID NO:41 (1 GS4 linker / spacer), or SEQ ID NO:143 (2 GS4 linkers / spacers) can be added to a VH of an antibody that can target TNF-α. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target cNF-kB. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target Sting. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target NLRP3. In an aspect, a disclosed 16- mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target TNF-α. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target IL-1α. In an aspect, a disclosed 16-mer PIGR- binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target IL-1β. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target IL-6. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target IL-7. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target IL-1b. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target IL-11. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target IL-33. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target Transglutaminase 2. In an aspect, a disclosed 16-mer PIGR-bindingPolsinelli 24-3026-WO peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can be added to a VH of an antibody that can target cNF-kB.

[0108] In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 can be linked to an antibody that recognizes and binds to PIK3CAH1047Rassociated with cancer (including breast cancer). In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 linked to an antibody that recognizes and binds to PIK3CAH1047Rcan be used in a method to treat a subject having cancer (including breast cancer). In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 can be linked to an antibody that recognizes and binds to PIK3CAE545Kassociated with cancer including breast cancer, prostate cancer, cervical cancer, non-small cell lung cancer, or colorectal cancer. In an aspect, a disclosed 16-mer PIGR- binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 linked to an antibody that recognizes and binds to PIK3CAE545Kcan be used in a method to treat a subject having cancer including breast cancer, prostate cancer, cervical cancer, non-small cell lung cancer, or colorectal cancer).

[0109] In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 can be linked to an antibody that recognizes and binds to BRAFVV600Eassociated with cancer. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 linked to an antibody that recognizes and binds to BRAFVV600Ecan be used in a method to treat a subject having cancer.

[0110] In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 can be linked to an antibody that recognizes and binds to BRAFV600Eassociated with cancer. In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 linked to an antibody that recognizes and binds to BRAFVV600Ecan be used in a method to treat a subject having cancer.

[0111] In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 can be linked to an antibody thatPolsinelli 24-3026-WO recognizes and binds to TP53R248Qassociated with cancer including prostate cancer, bladder cancer, pancreatic cancer, head and neck cancer, esophageal cancer, endometrial cancer, stomach cancer, cervical cancer, or any combination thereof. In an aspect, a disclosed 16-mer PIGR- binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 linked to an antibody that recognizes and binds to TP53R248Qcan be used in a method to treat a subject having prostate cancer, bladder cancer, pancreatic cancer, head and neck cancer, esophageal cancer, endometrial cancer, stomach cancer, cervical cancer, or any combination thereof.

[0112] In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 can be linked to an antibody that recognizes and binds to TP53R273Hassociated with cancer including breast cancer, colon cancer, head and neck cancer, ovarian cancer, or any combination thereof. In an aspect, a disclosed 16- mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 linked to an antibody that recognizes and binds to TP53R273Hcan be used in a method to treat a subject having breast cancer, colon cancer, head and neck cancer, ovarian cancer, or any combination thereof.

[0113] In an aspect, a disclosed 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 can be linked to an antibody that recognizes and binds to NRASQ61Kassociated with cancer. In an aspect, a disclosed 16-mer PIGR- binding peptide comprising the sequence set forth in SEQ ID NO:43 or SEQ ID NO:40 provided in Table 1 linked to an antibody that recognizes and binds to NRASQ61Kcan be used in a method to treat a subject having cancer. 2. Antibodies

[0114] Disclosed herein are anti-KRAS antibodies comprising an IgG backbone. Disclosed herein are anti-KRAS antibodies. In an aspect, a disclosed anti-KRAS antibody can comprise (i) a variable light chain region (VL) comprising 3 complementarity determining regions (CDRs), and (ii) a variable heavy chain region (VH) comprising 3 CDRs and a constant heavy chain region, wherein the VH is linked to a PIGR-binding peptide. As known to the skilled person, Polymeric Immunogloblin Receptor (PIGR) is a transmembrane protein that plays an important role in immunoglobulin transportation by facilitating transcytosis.

[0115] Disclosed herein is an anti-KRAS antibody comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) binding peptides, wherein the antibody recognizes the GTP-bound active form of KRAS. Disclosed herein is an antibody recognizing the GTP-bound active conformation of KRAS comprising an IgG backbone and one or more polymericPolsinelli 24-3026-WO immunoglobulin receptor (PIGR) binding peptides, wherein the antibody recognizes the GTP- bound active form of KRAS.

[0116] In an aspect, a disclosed IgG can comprise four polypeptide chains (i.e., two identical 50 kDa γ heavy (H) chains and two identical 25 kDa κ or λ light (L) chains - linked together by inter-chain disulfide bonds). In an aspect, a disclosed heavy chain can comprise an N-terminal variable domain (VH) and three constant domains (CH1, CH2, CH3) with an additional “hinge region” between CH1 and CH2. In an aspect, a disclosed light chain can comprise an N-terminal variable domain (VL) and a constant domain (CL). In an aspect, a disclosed light chain can associate with the VH and CH1 domains to form a Fab arm (“Fab” = fragment antigen binding). In an aspect, disclosed V regions can interact to form the in antigen-binding region – acquired through differential assembly of Variable, Diversity (VH only), and Joining gene segments and inclusion of somatic mutations. In an aspect, two heavy chain–light chain heterodimers (HL) can combine into a single antibody molecule (H2L2) via disulfide bonds in the hinge region and non- covalent interactions between the CH3 domains. In an aspect, the part of the antibody formed by the lower hinge region and the CH2 / CH3 domains is called “Fc” (“fragment crystalline”).

[0117] In an aspect, a disclosed KRAS can be a mutant KRAS or a KRAS having one or more mutations. In an aspect, a disclosed mutant KRAS can comprise KRASG12A, KRASG12C, KRASG12D, KRASG12R, KRASG12S, KRASG12V, KRASG12X, KRASG13C, KRASG13D, KRASG13X, KRASQ61H, KRASQ61L, KRASQ61K, KRASQ61R, KRASQ61X, KRASA146T, KRASA146V, KRASA146X, or any combination thereof.

[0118] In an aspect, a disclosed anti-KRAS antibody can comprise (i) a variable light chain region (VL) comprising 3 complementarity determining regions (CDRs), and (ii) a variable heavy chain region (VH) comprising 3 CDRs and a constant heavy chain region, wherein the VH is linked to a PIGR-binding peptide.

[0119] PIGR-binding peptides are discussed supra. Variable Light Chain (VL)

[0120] Disclosed herein is a VL comprising the sequence set forth in SEQ ID NO:18. Disclosed herein is a VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18. Disclosed herein is an anti-KRAS antibody comprising a VL comprising the sequence set forth in SEQ ID NO:18. Disclosed herein is an anti-KRAS antibody comprising a VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18.Polsinelli 24-3026-WO

[0121] Disclosed herein is a VL comprising the sequence set forth in SEQ ID NO:18 or a fragment thereof. Disclosed herein is a VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VL comprising the sequence set forth in SEQ ID NO:18 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18 or a fragment thereof.

[0122] Disclosed herein is a VL comprising the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27. Disclosed herein is a VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27. Disclosed herein is an anti- KRAS antibody comprising a VL comprising the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27. Disclosed herein is an anti-KRAS antibody comprising a VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27.

[0123] Disclosed herein is a VL comprising the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27 or a fragment thereof. Disclosed herein is a VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VL comprising the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27 or a fragment thereof.

[0124] In an aspect, a disclosed VL can be part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VL comprising the sequence set forth in SEQ ID NO:18 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VL comprising the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%,Polsinelli 24-3026-WO or more than 95% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27 can be a part of a disclosed anti-KRAS antibody.

[0125] In an aspect, a disclosed VL comprising the sequence set forth in SEQ ID NO:18 or a fragment thereof can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18 or a fragment thereof can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VL comprising the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27 or a fragment thereof can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27 or a fragment thereof can be a part of a disclosed anti-KRAS antibody.

[0126] In an aspect, a disclosed VL comprising the sequence set forth in SEQ ID NO:18 can be encoded by the sequence set forth in SEQ ID NO:20. In an aspect, a disclosed VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18 can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:20. In an aspect, a disclosed VL comprising the sequence set forth in SEQ ID NO:18 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:20 or a fragment thereof. In an aspect, a disclosed VL comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18 or a fragment thereof can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:20 or a fragment thereof.

[0127] In an aspect, a disclosed VL can comprise a 5’ signal peptide. In an aspect of a disclosed VL, a disclosed signal peptide can be any signal peptide. Signal peptides are known to the art. In an aspect, a disclosed VL can start with a disclosed signal peptide (SP). In an aspect, a disclosed signal peptide can be located at the N terminus of a protein and can carry information for protein post-translational assembly in the endoplasmic reticulum (ER) and Golgi organelle and expression on the membrane. In an aspect, a disclosed SP can be located at the N terminus of a nascent VL can be identified by the signal recognition particle (SRP) while the protein is still translating in the ribosome. In an aspect, after a disclosed nascent VL crosses the ER membrane, the signal peptide is cleaved off by a signal peptide peptidase (SPP). In an aspect, a disclosed signal peptide canPolsinelli 24-3026-WO comprise any known signal peptide or any known signal peptide that functions in mammalian cells.

[0128] In an aspect, a disclosed signal peptide can comprise the sequence set forth in SEQ ID NO:51. In an aspect, a disclosed signal peptide comprising the sequence set forth in SEQ ID NO:51 can be encoded by the sequence set forth in SEQ ID NO:52. In an aspect, a disclosed signal peptide can comprise the sequence set forth in any one of SEQ ID NO:53 – SEQ ID NO:56. In an aspect, a disclosed signal peptide comprising the sequence set forth in SEQ ID NO:53 can be encoded by the sequence set forth in SEQ ID NO:57. In an aspect, a disclosed VL having a signal peptide can comprise the sequence set forth in SEQ ID NO:17. In an aspect, a disclosed VL having a signal peptide can comprise the sequence set forth in SEQ ID NO:17 or a fragment thereof. In an aspect, a disclosed VL having a signal peptide can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:17. In an aspect, a disclosed VL having a signal peptide can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:17 or a fragment thereof.

[0129] In an aspect, a disclosed VL having a signal peptide comprising the sequence set forth in SEQ ID NO:17 can be encoded by the sequence set forth in SEQ ID NO:19. In an aspect, a disclosed VL having a signal peptide comprising the sequence set forth in SEQ ID NO:17 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:19 or a fragment thereof. In an aspect, a disclosed VL having a signal peptide comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:17 can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:19. In an aspect, a disclosed VL having a signal peptide comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:17 or a fragment thereof can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:19 or a fragment thereof. CDRs in the VL

[0130] In an aspect, each CDR in the VL can comprise the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66. In an aspect, a CDR in the VL can comprise the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66. In an aspect,Polsinelli 24-3026-WO each CDR in the VL can comprise a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66. In an aspect, a CDR in the VL can comprise a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66. In an aspect, a disclosed VL can comprise a CDR comprising the sequence set forth in SEQ ID NO:64, a CDR comprising the sequence set forth in SEQ ID NO:65, and a CDR comprising the sequence set forth in SEQ ID NO:66. In an aspect, a disclosed VL can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:64, and (ii) at least two other disclosed CDRs. In an aspect, a disclosed VL can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:65, and (ii) at least two other disclosed CDRs. In an aspect, a disclosed VL can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:66, and (ii) at least two other disclosed CDRs.

[0131] In an aspect, a disclosed CDR can comprise the sequence set forth in any one of SEQ ID NO:102 – SEQ ID NO:124. In an aspect, a disclosed VL can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:64, and (ii) at least two other disclosed CDRs comprising the sequence set forth in any one of SEQ ID NO:102 – SEQ ID NO:124. In an aspect, a disclosed VL can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:65, and (ii) at least two other disclosed CDRs comprising the sequence set forth in any one of SEQ ID NO:102 – SEQ ID NO:124. In an aspect, a disclosed VL can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:66, and (ii) at least two other disclosed CDRs comprising the sequence set forth in any one of SEQ ID NO:102 – SEQ ID NO:124.

[0132] In an aspect, a disclosed VL comprising the sequence set of SEQ ID NO:17 can comprise one or more disclosed CDRs. In an aspect, a disclosed VL comprising the sequence set of SEQ ID NO:17 can comprise the CDRs set forth in any one of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66. In an aspect, a CDR in the VL can comprise a sequence having between about 60% and about 70% identity or between about 70% and about 80% identity to the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66.

[0133] In an aspect, a disclosed VL can comprise a CDR that is evolved to differ by at least 20% from the sequence set forth in any one of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66.

[0134] In an aspect, choosing the amino acid substitutions for a disclosed CDR can be informed by Gonzalez-Munoz et al. (2012) MAbs.4(6):664-672, which is incorporated herein in its entirety for its teaching of tailoring amino acid diversity for the evolution of antibody affinity.

[0135] In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:64 can be encoded by the sequence set forth in SEQ ID NO:67. In an aspect, a CDR comprising the sequence setPolsinelli 24-3026-WO forth in SEQ ID NO:65 can be encoded by the sequence set forth in SEQ ID NO:68. In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:66 can be encoded by the sequence set forth in SEQ ID NO:69. In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:64 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:67 or a fragment thereof. In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:65 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:68 or a fragment thereof. In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:66 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:69 or a fragment thereof.

[0136] In an aspect, a disclosed VL can comprise one or more CDRs listed in Table 2. In an aspect, a disclosed VL can comprise two or more CDRs listed in Table 2. In an aspect, a disclosed VL can comprise three CDRs listed in Table 2. TABLE 2 – Exemplary CDRs for VL

[0137] In an aspect, a disclosed VL can comprise a VL listed in Table 3 or a fragment thereof. In an aspect, a disclosed VL can comprise a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to a VL sequence listed in Table 3 or a fragment thereof. TABLE 3 – Exemplary VL Sequences of Anti-KRAS AntibodyPolsinelli 24-3026-WO

[0138] In an aspect, a VL listed in Table 3 or a fragment thereof can further comprise a disclosed signal peptide. Variable Heavy Chain (VH)

[0139] Disclosed herein is a VH comprising a 20-mer PIGR-binding peptide. Disclosed herein is a VH comprising the sequence set forth in SEQ ID NO:05. Disclosed herein is a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05. Disclosed herein is an anti- KRAS antibody comprising a VH comprising the sequence set forth in SEQ ID NO:05. Disclosed herein is an anti-KRAS antibody comprising a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05.Polsinelli 24-3026-WO

[0140] Disclosed herein is a VH comprising the sequence set forth in SEQ ID NO:05 or a fragment thereof. Disclosed herein is a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VH comprising the sequence set forth in SEQ ID NO:05 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05 or a fragment thereof.

[0141] In an aspect, a disclosed VH comprising a 20-mer PIGR-binding peptide can be part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:05 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:05 or a fragment thereof can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05 or a fragment thereof can be a part of a disclosed anti-KRAS antibody.

[0142] In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:05 can be encoded by the sequence set forth in SEQ ID NO:08. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05 can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:08. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:05 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:08 or a fragment thereof.

[0143] In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05 or a fragment thereof can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:08 or a fragment thereof.

[0144] Disclosed herein is a VH comprising a 16-mer PIGR-binding peptide. Disclosed herein is a VH comprising the sequence set forth in SEQ ID NO:06. Disclosed herein is a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%,Polsinelli 24-3026-WO or more than 95% identity to the sequence set forth in SEQ ID NO:06. Disclosed herein is an anti- KRAS antibody comprising a VH comprising the sequence set forth in SEQ ID NO:06. Disclosed herein is an anti-KRAS antibody comprising a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:06. Disclosed herein is a VH comprising the sequence set forth in SEQ ID NO:06 or a fragment thereof. Disclosed herein is a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:06 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VH comprising the sequence set forth in SEQ ID NO:06 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:06 or a fragment thereof.

[0145] In an aspect, a disclosed VH comprising a 16-mer PIGR-binding peptide can be part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:06 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:06 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:06 or a fragment thereof can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:06 or a fragment thereof can be a part of a disclosed anti-KRAS antibody.

[0146] In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:06 can be encoded by the sequence set forth in SEQ ID NO:09. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:06 can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:09. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:05 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:09 or a fragment thereof. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:06 or a fragment thereof can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%,Polsinelli 24-3026-WO at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:09 or a fragment thereof.

[0147] Disclosed herein is a VH comprising a 12-mer PIGR-binding peptide. Disclosed herein is a VH comprising the sequence set forth in SEQ ID NO:07. Disclosed herein is a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:07. Disclosed herein is an anti- KRAS antibody comprising a VH comprising the sequence set forth in SEQ ID NO:07. Disclosed herein is an anti-KRAS antibody comprising a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:07.

[0148] Disclosed herein is a VH comprising the sequence set forth in SEQ ID NO:07 or a fragment thereof. Disclosed herein is a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:07 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VH comprising the sequence set forth in SEQ ID NO:07 or a fragment thereof. Disclosed herein is an anti-KRAS antibody comprising a VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:07 or a fragment thereof.

[0149] In an aspect, a disclosed VH comprising a 12-mer PIGR-binding peptide can be part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:07 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:07 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:07 or a fragment thereof can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:07 or a fragment thereof can be a part of a disclosed anti-KRAS antibody.

[0150] In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:07 can be encoded by the sequence set forth in SEQ ID NO:10. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:07 can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:10. In an aspect, a disclosedPolsinelli 24-3026-WO VH comprising the sequence set forth in SEQ ID NO:07 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:10 or a fragment thereof. In an aspect, a disclosed VH comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:07 or a fragment thereof can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:10 or a fragment thereof.

[0151] In an aspect, a disclosed VH can comprise a 5’ signal peptide. In an aspect of a disclosed VH, a disclosed signal peptide can be any signal peptide. Signal peptides are known to the art. In an aspect, a disclosed VH can start with a disclosed signal peptide (SP). In an aspect, a disclosed signal peptide can be located at the N terminus of a protein and can carry information for protein post-translational assembly in the endoplasmic reticulum (ER) and Golgi organelle and expression on the membrane. In an aspect, a disclosed SP can be located at the N terminus of a nascent VH can be identified by the signal recognition particle (SRP) while the protein is still translating in the ribosome. In an aspect, after a disclosed nascent VH crosses the ER membrane, the signal peptide is cleaved off by a signal peptide peptidase (SPP). In an aspect, a disclosed signal peptide can comprise any known signal peptide or any known signal peptide known to function in mammalian cells.

[0152] In an aspect of a disclosed VH, a disclosed signal peptide can comprise the sequence set forth in SEQ ID NO:51. In an aspect of a disclosed VH, a disclosed signal peptide comprising the sequence set forth in SEQ ID NO:51 can be encoded by the sequence set forth in SEQ ID NO:52. In an aspect of a disclosed VH, a disclosed signal peptide can comprise the sequence set forth in any one of SEQ ID NO:53 – SEQ ID NO:56. In an aspect of a disclosed VH, a disclosed signal peptide comprising the sequence set forth in SEQ ID NO:53 can be encoded by the sequence set forth in SEQ ID NO:57.

[0153] In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:05 can further comprise a signal peptide having the sequence set forth in SEQ ID NO:51. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:05 or a fragment thereof can further comprise a signal peptide having the sequence set forth in SEQ ID NO:51 or a fragment thereof.

[0154] In an aspect, a disclosed VH having a signal peptide can comprise the sequence set forth in SEQ ID NO:11. In an aspect, a disclosed VH having a signal peptide can comprise the sequence set forth in SEQ ID NO:11 or a fragment thereof. In an aspect, a disclosed VH having a signal peptide can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:11. InPolsinelli 24-3026-WO an aspect, a disclosed VH having a signal peptide can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:11 or a fragment thereof.

[0155] In an aspect, a disclosed VH having a signal peptide comprising the sequence set forth in SEQ ID NO:11 can be encoded by the sequence set forth in SEQ ID NO:14. In an aspect, a disclosed VH having a signal peptide comprising the sequence set forth in SEQ ID NO:11 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:14 or a fragment thereof. In an aspect, a disclosed VH having a signal peptide comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:11 can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:14. In an aspect, a disclosed VH having a signal peptide comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:11 or a fragment thereof can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:14 or a fragment thereof.

[0156] In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:06 can further comprise a signal peptide having the sequence set forth in SEQ ID NO:51. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:06 or a fragment thereof can further comprise a signal peptide having the sequence set forth in SEQ ID NO:51 or a fragment thereof.

[0157] In an aspect, a disclosed VH having a signal peptide can comprise the sequence set forth in SEQ ID NO:12. In an aspect, a disclosed VH having a signal peptide can comprise the sequence set forth in SEQ ID NO:12 or a fragment thereof. In an aspect, a disclosed VH having a signal peptide can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:12. In an aspect, a disclosed VH having a signal peptide can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:12 or a fragment thereof.

[0158] In an aspect, a disclosed VH having a signal peptide comprising the sequence set forth in SEQ ID NO:12 can be encoded by the sequence set forth in SEQ ID NO:15. In an aspect, a disclosed VH having a signal peptide comprising the sequence set forth in SEQ ID NO:12 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:15 or a fragment thereof. In an aspect, a disclosed VH having a signal peptide comprising a sequence having at least 70%,Polsinelli 24-3026-WO at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:12 can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:15. In an aspect, a disclosed VH having a signal peptide comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:12 or a fragment thereof can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:12 or a fragment thereof.

[0159] In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:07 can further comprise a signal peptide having the sequence set forth in SEQ ID NO:51. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:07 or a fragment thereof can further comprise a signal peptide having the sequence set forth in SEQ ID NO:51 or a fragment thereof. In an aspect, a disclosed VH having a signal peptide can comprise the sequence set forth in SEQ ID NO:13. In an aspect, a disclosed VH having a signal peptide can comprise the sequence set forth in SEQ ID NO:13 or a fragment thereof. In an aspect, a disclosed VH having a signal peptide can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:13. In an aspect, a disclosed VH having a signal peptide can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:13 or a fragment thereof.

[0160] In an aspect, a disclosed VH having a signal peptide comprising the sequence set forth in SEQ ID NO:13 can be encoded by the sequence set forth in SEQ ID NO:16. In an aspect, a disclosed VH having a signal peptide comprising the sequence set forth in SEQ ID NO:13 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:16 or a fragment thereof. In an aspect, a disclosed VH having a signal peptide comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:13 can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:16. In an aspect, a disclosed VH having a signal peptide comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:13 or a fragment thereof can be encoded by a sequence having at least 70%, at least 75%, at least 80%, at least 85%,Polsinelli 24-3026-WO at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:16 or a fragment thereof.

[0161] Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide. Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide. Disclosed herein is a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR- binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR- binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide.

[0162] Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR- binding peptide, or a 12-mer PIGR-binding peptide. Disclosed herein is a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide. In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide can be part of a disclosed anti-KRAS antibody.Polsinelli 24-3026-WO

[0163] In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR- binding peptide, or a 12-mer PIGR-binding peptide can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide can be a part of a disclosed anti-KRAS antibody.

[0164] Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42. Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42. Disclosed herein is a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20- mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42. Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42. Disclosed herein is a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or morePolsinelli 24-3026-WO than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42.

[0165] In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42 can be part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42 can be a part of a disclosed anti-KRAS antibody.

[0166] In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 20-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39 or SEQ ID NO:42 can be a part of a disclosed anti-KRAS antibody.

[0167] Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43. Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43. Disclosed herein is a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at leastPolsinelli 24-3026-WO 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43.

[0168] Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43.

[0169] Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43. Disclosed herein is a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43.

[0170] Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43.

[0171] In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43 can be part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one ofPolsinelli 24-3026-WO SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43 can be a part of a disclosed anti-KRAS antibody.

[0172] In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 16-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:40 or SEQ ID NO:43 can be a part of a disclosed anti-KRAS antibody.

[0173] Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143.

[0174] Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143. Disclosed herein is a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143.

[0175] Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143.

[0176] Disclosed herein is a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143. Disclosed herein is a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ IDPolsinelli 24-3026-WO NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143.

[0177] Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143. Disclosed herein is an anti-KRAS antibody comprising a VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143.

[0178] In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143 can be part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143 can be a part of a disclosed anti- KRAS antibody.

[0179] In an aspect, a disclosed VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143 can be a part of a disclosed anti-KRAS antibody. In an aspect, a disclosed VH comprising (i) a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; and (ii) a 12-mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44, or SEQ ID NO:143 can be a part of a disclosed anti-KRAS antibody.

[0180] In an aspect, a disclosed VH comprising (i) the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 or a fragment thereof; (ii) a GS4 linker (SEQ ID NO:142); and (iii) a 12- mer PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41, SEQ ID NO:44. In an aspect, a disclosed 12-mer PIGR-binding peptide can comprise the sequence of SEQ IDPolsinelli 24-3026-WO NO:41 and a GS4 linker (SEQ ID NO:142). In an aspect, SEQ ID NO:143 comprises SEQ ID NO:41 and SEQ ID NO:142. CDRs in the VH

[0181] In an aspect of a disclosed anti-KRAS antibody, each CDR in the VH can comprise the sequence set forth in any one of SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60. In an aspect, a CDR in the VH can comprise the sequence set forth in any one of SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60. In an aspect, each CDR in the VH can comprise a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60. In an aspect, a CDR in the VH can comprise a sequence having at least 70%, at least 75%, or at least 80% identity to the sequence set forth in any one of SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60. In an aspect, a disclosed VH can comprise a CDR comprising the sequence set forth in SEQ ID NO:58, a CDR comprising the sequence set forth in SEQ ID NO:59, and a CDR comprising the sequence set forth in SEQ ID NO:60. In an aspect, a disclosed VH can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:58, and (ii) at least two other disclosed CDRs. In an aspect, a disclosed VH can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:59, and (ii) at least two other disclosed CDRs. In an aspect, a disclosed VH can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:60, and (ii) at least two other disclosed CDRs.

[0182] In an aspect, a disclosed CDR can comprise the sequence set forth in any one of SEQ ID NO:70 – SEQ ID NO:101. In an aspect, a disclosed VH can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:58, and (ii) at least two other disclosed CDRs comprising the sequence set forth in any one of SEQ ID NO:70 – SEQ ID NO:101. In an aspect, a disclosed VH can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:59, and (ii) at least two other disclosed CDRs comprising the sequence set forth in any one of SEQ ID NO:70 – SEQ ID NO:101. In an aspect, a disclosed VH can comprise (i) a CDR comprising the sequence set forth in SEQ ID NO:60, and (ii) at least two other disclosed CDRs comprising the sequence set forth in any one of SEQ ID NO:70 – SEQ ID NO:101.

[0183] In an aspect, a disclosed VH comprising the sequence set of SEQ ID NO:05 can comprise one or more disclosed CDRs. In an aspect, a disclosed VH comprising the sequence set of SEQ ID NO:05 can comprise the CDRs set forth in any one of SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60. In an aspect, a disclosed VH comprising the sequence set of SEQ ID NO:06 can comprise one or more disclosed CDRs. In an aspect, a disclosed VH comprising the sequence set of SEQ ID NO:06 can comprise the CDRs set forth in any one of SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60. In an aspect, a disclosed VH comprising the sequence set of SEQ ID NO:07Polsinelli 24-3026-WO can comprise one or more disclosed CDRs. In an aspect, a disclosed VH comprising the sequence set of SEQ ID NO:07 can comprise the CDRs set forth in any one of SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60.

[0184] In an aspect of a disclosed anti-KRAS antibody, a CDR in the VH can comprise a sequence having between about 60% and about 70% identity or between about 70% and about 80% identity to the sequence set forth in any one of SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60. In an aspect, a disclosed anti-KRAS antibody can comprise a CDR that is evolved to differ by at least 20% from the sequence set forth in any one of SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60.

[0185] In an aspect, choosing the amino acid substitutions for a disclosed CDR can be informed by Gonzalez-Munoz et al. (2012) MAbs.4(6):664-672, which is incorporated herein in its entirety for its teaching of tailoring amino acid diversity for the evolution of antibody affinity.

[0186] In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:58 can be encoded by the sequence set forth in SEQ ID NO:61. In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:59 can be encoded by the sequence set forth in SEQ ID NO:62. In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:60 can be encoded by the sequence set forth in SEQ ID NO:63. In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:64 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:67 or a fragment thereof. In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:65 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:68 or a fragment thereof. In an aspect, a CDR comprising the sequence set forth in SEQ ID NO:66 or a fragment thereof can be encoded by the sequence set forth in SEQ ID NO:69 or a fragment thereof.

[0187] In an aspect, a disclosed VH can comprise one or more CDRs listed in Table 4. In an aspect, a disclosed VH can comprise two or more CDRs listed in Table 4. In an aspect, a disclosed VH can comprise three CDRs listed in Table 4. In an aspect, a disclosed VL can comprise a VL listed in Table 4 or a fragment thereof. In an aspect, a disclosed VL can comprise a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to a VL sequence listed in Table 4 or a fragment thereof. TABLE 4 – Exemplary CDRs for VHPolsinelli 24-3026-WO

[0188] In an aspect, a disclosed VH can comprise a VH listed in Table 5 or a fragment thereof. In an aspect, a disclosed VH can comprise a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to a VH sequence listed in Table 5 or a fragment thereof. TABLE 5 – Exemplary VH Sequences with PIGR-Binding Peptide of Anti-KRAS AntibodyPolsinelli 24-3026-WO

[0189] In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:05 can be encoded by SEQ ID NO:08. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:06 can be encoded by SEQ ID NO:09. In an aspect, a disclosed VH comprising the sequence set forth in SEQ ID NO:07 can be encoded by SEQ ID NO:10.

[0190] In an aspect, a disclosed VH can comprise a VH listed in Table 6 or a fragment thereof. In an aspect, a disclosed VH can comprise a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to a VH sequence listed in Table 6 or a fragment thereof. In an aspect, a disclosed PIGR-binding peptide can be added to a VH disclosed in Table 6. In an aspect, a disclosed PIGR-binding peptide can be a PIGR-binding peptide listed in Table 1. TABLE 6 – Exemplary VH Sequences (without PIGR-Binding Peptide) of Anti-KRAS AntibodyPolsinelli 24-3026-WOPolsinelli 24-3026-WO

[0191] Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:05. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:05. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL having the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH having a PIGR-binding peptide having the sequence set forth in SEQ ID NO:05. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH comprising a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:05.

[0192] Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:17, and (ii) a VH comprising a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:13. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR- binding peptide and comprising the sequence set forth in SEQ ID NO:10.

[0193] Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:06. Disclosed herein is an anti-KRAS antibody, comprising: (i)Polsinelli 24-3026-WO a VL comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:18, and (ii) a VH having a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:06. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH having a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:06. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH comprising a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:06.

[0194] Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in SEQ ID NO:18, and (ii) a VH comprising a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:07. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:18, and (ii) a VH having a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:07. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH having a PIGR-binding peptide and comprising the sequence set forth in SEQ ID NO:07. Disclosed herein is an anti-KRAS antibody, comprising: (i) a VL comprising a sequence having at least 80% identity to the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and (ii) a VH comprising a PIGR-binding peptide and comprising a sequence having at least 80% identity to the sequence set forth in SEQ ID NO:07.

[0195] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise a PIGR-binding peptide. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise a 20-mer PIGR-binding peptide, a 16-mer PIGR- binding peptide, or a 12-mer PIGR-binding peptide. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise a PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39, SEQ ID NO:40, or SEQ ID NO:41. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise a PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41 or SEQ ID NO:143.

[0196] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise a PIGR-binding peptide.Polsinelli 24-3026-WO In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide.

[0197] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise a 12-mer PIGR-binding peptide. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise a 12-mer PIGR-binding peptide comprising the sequence of SEQ ID NO:41 or SEQ ID NO:143.

[0198] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise the sequence set forth in SEQ ID NO:05, SEQ ID NO:06, or SEQ ID NO:07. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise the sequence set forth in SEQ ID NO:07. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL comprising the sequence set forth in SEQ ID NO:18 can be encoded by the sequence set forth in SEQ ID NO:20, and a disclosed VH comprising the sequence set forth in SEQ ID NO:05, SEQ ID NO:06, or SEQ ID NO:07 can be encoded by the sequence set forth in SEQ ID NO:08, SEQ ID NO:09, or SEQ ID NO:10. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL comprising the sequence set forth in SEQ ID NO:18 can be encoded by the sequence set forth in SEQ ID NO:20, and a disclosed VH comprising the sequence set forth in SEQ ID NO:07 can be encoded by the sequence set forth in SEQ ID NO:10.

[0199] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL having a signal peptide can comprise the sequence set forth in SEQ ID NO:17. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL having a signal peptide and comprising the sequence set forth in SEQ ID NO:17 can be encoded by the sequence set forth in SEQ ID NO:19. In an aspect of a disclosed anti-KRAS antibody, a disclosed VH having a 20-mer PIGR-binding peptide and having a signal peptide can comprise the sequence set forth in SEQ ID NO:11. In an aspect of a disclosed anti- KRAS antibody, a disclosed VH having a 20-mer PIGR-binding peptide and having a signal peptide and comprising the sequence set forth in SEQ ID NO:11 can be encoded by the sequence set forth in SEQ ID NO:14.

[0200] In an aspect of a disclosed anti-KRAS antibody, a disclosed VH having a 16-mer PIGR- binding peptide and having a signal peptide can comprise the sequence set forth in SEQ ID NO:12.Polsinelli 24-3026-WO In an aspect of a disclosed anti-KRAS antibody, a disclosed VH having a 16-mer PIGR-binding peptide and having a signal peptide and comprising the sequence set forth in SEQ ID NO:12 can be encoded by the sequence set forth in SEQ ID NO:15.

[0201] In an aspect of a disclosed anti-KRAS antibody, a disclosed VH having a 12-mer PIGR- binding peptide and having a signal peptide can comprise the sequence set forth in SEQ ID NO:13. In an aspect of a disclosed anti-KRAS antibody, a disclosed VH having a 12-mer PIGR-binding peptide and having a signal peptide and comprising the sequence set forth in SEQ ID NO:13 can be encoded by the sequence set forth in SEQ ID NO:16.

[0202] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise the sequence set forth in SEQ ID NO:05, SEQ ID NO:06, or SEQ ID NO:07. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise the sequence set forth in SEQ ID NO:07.

[0203] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise a PIGR- binding peptide. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR- binding peptide. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise a PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39, SEQ ID NO:40, or SEQ ID NO:41.

[0204] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise a PIGR- binding peptide comprising the sequence set forth in SEQ ID NO:41 or SEQ ID NO:143.

[0205] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 and a PIGR-binding peptide. In an aspect of a disclosed anti- KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 and a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding domain, or a 12-mer PIGR-binding domain. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise the sequence set forth inPolsinelli 24-3026-WO any one of SEQ ID NO:28 – SEQ ID NO:38 and a PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, or SEQ ID NO:143. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in SEQ ID NO:18, and a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 and a PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41 or SEQ ID NO:143.

[0206] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise a PIGR- binding peptide comprising the sequence set forth in SEQ ID NO:39, SEQ ID NO:40, or SEQ ID NO:41. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise a PIGR- binding peptide comprising the sequence set forth in SEQ ID NO:41 or SEQ ID NO:143.

[0207] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise the sequence set forth in SEQ ID NO:05, SEQ ID NO:06, or SEQ ID NO:07. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise the sequence set forth in SEQ ID NO:07.

[0208] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 and a PIGR-binding peptide.

[0209] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 and a 20-mer PIGR-binding peptide, a 16-mer PIGR-binding peptide, or a 12-mer PIGR-binding peptide.

[0210] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 and a PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, or SEQ ID NO:143. In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise the sequence set forth in any one of SEQ ID NO:21 – SEQ ID NO:27, and a disclosed VH can comprise the sequence set forth in any one of SEQ ID NO:28 – SEQ ID NO:38 and a PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41 or SEQ ID NO:143.Polsinelli 24-3026-WO

[0211] In an aspect of a disclosed anti-KRAS antibody, a disclosed VL can comprise 3 CDRs. In an aspect, a disclosed VL can comprise 3 CDRs selected from Table 2. In an aspect, a disclosed VL can comprise 3 CDRs, wherein the 3 CDRs comprise SEQ ID NO:64, SEQ ID NO:65, or SEQ ID NO:66. In an aspect, a disclosed VL can comprise 3 CDRs, wherein the 3 CDRs are selected from SEQ ID NO:102 – SEQ ID NO:124. In an aspect, a disclosed VL can comprise 3 CDRs, wherein the 3 CDRs are selected from SEQ ID NO:64 – SEQ ID NO:66 and SEQ ID NO:102 – SEQ ID NO:124.

[0212] In an aspect of a disclosed anti-KRAS antibody, a disclosed VH can comprise 3 CDRs. In an aspect, a disclosed VH can comprise 3 CDRs selected from Table 3. In an aspect, a disclosed VH can comprise 3 CDRs, wherein the 3 CDRs comprise SEQ ID NO:58, SEQ ID NO:59, or SEQ ID NO:60. In an aspect, a disclosed VH can comprise 3 CDRs, wherein the 3 CDRs are selected from SEQ ID NO:70 - SEQ ID NO:101. In an aspect, a disclosed VH can comprise 3 CDRs, wherein the 3 CDRs are selected from SEQ ID NO:58 – SEQ ID NO:60 and SEQ ID NO:70 – SEQ ID NO:101. In an aspect, a disclosed VH can comprise 3 CDRs, having the sequence set forth in SEQ ID NO:58, SEQ ID NO:59, and SEQ ID NO:60, and disclosed VL can comprise 3 CDRs having the sequence set forth in SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66.

[0213] In an aspect of an anti-KRAS antibody, a disclosed VL can comprise 3 complementarity determining regions (CDRs), and a disclosed VH can comprise 3 CDRs, wherein the VH is linked a PIGR-binding peptide.

[0214] In an aspect, a disclosed spacer can be a GS-based spacer sequence (such as, for example, GGGGS – SEQ ID NO:142). In an aspect, a disclosed spacer can be a rigid spacer or a flexible spacer. In an aspect, a disclosed spacer can be a glycine-serine linker or an aspartic acid-proline spacer. By adjusting the copy number “n” of a flexible linker, the length of a GS-based linker can be optimized to achieve appropriate separation of the functional domains, maintain necessary inter-domain interactions, and allow for proper folding of the fusion proteins. In an aspect, a disclosed rigid linker.

[0215] Disclosed herein in an antibody having an IgG backbone and a PIGR-binding peptide that binds to PIGR expressed on the surface of a cancer cell, thereby allowing internalization of the antibody that targets an intracellular target associated with the development and / or progression of cancer. In an aspect, the internalization of the antibody due to the interaction of the PIGR-binding peptide can facilitate the interaction between the antibody and the intracellular target, thereby killing the cancer cell and / or decreasing the ability of the cancer to thrive or divide.

[0216] Disclosed herein is an anti-KRAS antibody having an IgG backbone comprising any disclosed VL including, for example, those listed in Table 3. Disclosed herein is an anti-KRASPolsinelli 24-3026-WO antibody having an IgG backbone comprising any disclosed VH including, for example, those listed in Table 5. Disclosed herein is an anti-KRAS antibody having an IgG backbone comprising any disclosed VH including, for example, those listed in Table 6 with a disclosed PIGR-binding peptide including, for example, those disclosed in Table 1. Disclosed herein is an anti-KRAS antibody having an IgG backbone comprising a VL comprising any disclosed CDR including, for example, those listed in Table 2. Disclosed herein is an anti-KRAS antibody having an IgG backbone comprising a VH comprising any disclosed CDR including, for example, those listed in Table 4. Disclosed herein is an anti-KRAS antibody having an IgG backbone comprising a combination of any disclosed VL and any disclosed VH, such as, for example, those disclosed in Table 3 and Table 5. Disclosed herein is an anti-KRAS antibody having an IgG backbone comprising a combination of any disclosed VL and any disclosed VH, such as, for example, those disclosed in Table 3 and Table 6 (with a disclosed PIGR such as, those listed in Table 1). Disclosed herein is an anti-KRAS antibody having an IgG backbone comprising a VL and a VH, each comprising a combination of any disclosed CDRs such as, for example, those disclosed in Table 2 or Table 4.

[0217] In an aspect, a disclosed antibody can be used to induce and / or facilitate transcytosis. In an aspect, a disclosed antibody (following the binding to PIGR expressed on a cancer cell) can be transported across the vascular endothelium and into a solid tumor (e.g., involving uptake, intracellular transport and exocytosis). In an aspect, a disclosed anti-KRAS antibody can slow or can prevent tumor growth. In an aspect, a disclosed anti-KRAS antibody can recognize the GTP- bound active form of KRAS. In an aspect, a disclosed anti-KRAS antibody can bind intracellular KRAS and can promote the expulsion of the mutant KRAS from the cytoplasm of the tumor cell.

[0218] In an aspect, a disclosed PIGR-binding peptide can bind to one or more of D1, D2, D3, D4, and D5 of the extracellular domain of PIGR or a portion thereof. In an aspect, a disclosed anti- KRAS antibody can comprise a means for binding PIGR on one or more cancer cells characterized by expression of a KRAS. In an aspect, a disclosed anti-KRAS antibody can comprise a means for binding PIGR on one or more cancer cells characterized by expression of KRAS, wherein the means for biding PIGR can comprise a PIGR-binding peptide. In an aspect, a disclosed anti-KRAS antibody can comprise a means for binding PIGR on one or more cancer cells characterized by expression of KRAS, wherein the means for biding PIGR can comprise a disclosed 20-mer, a disclosed 16-mer, or a disclosed 12-mer PIGR-binding peptide. In an aspect, a disclosed anti- KRAS antibody can comprise a means for binding PIGR on one or more cancer cells characterized by expression of KRAS, wherein the means for biding PIGR can comprise a PIGR-binding peptide comprising the sequence set forth in SEQ ID NO:41 or SEQ ID NO:143.Polsinelli 24-3026-WO

[0219] In an aspect of a disclosed anti-KRAS antibody, the binding of the one or more PIGR- binding peptides to PIGR on a cell triggers transcytosis of the disclosed antibody into the cell. In an aspect of a disclosed anti-KRAS antibody, a disclosed IgG backbone can comprise an IgG1 backbone, an IgG2 backbone, an IgG3 backbone, or an IgG4 backbone. In an aspect, a disclosed anti-KRAS antibody can extend the anti-tumor activity.

[0220] In an aspect, a disclosed anti-KRAS antibody can be used in a disclosed method. In an aspect, a disclosed anti-KRAS antibody can be used in a disclosed method of treating a subject having cancer. In an aspect, a disclosed anti-KRAS antibody can be used in a disclosed method of slowing disease progression in a subject having cancer. In an aspect, a disclosed anti-KRAS antibody can be used in a method of treating a subject having pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, bladder adenocarcinoma, endometroid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, colorectal adenocarcinoma, or pancreatic carcinoma. In an aspect, a disclosed anti-KRAS antibody can induce PIGR mediated transcytosis in one or more cells including, for example, one or more cancer cells and / or one or more tumor cells. In an aspect, a disclosed anti-KRAS antibody can be used to (i) prevent and / or decrease the risk of developing metastases, (ii) prolong the survival of the subject, (iii) enhance and / or improve the subject’s quality of life, (iv) reduce and / or minimize the likelihood of surgical intervention, (v) reduce and / or decrease the size of one or more tumors in the subject, (vi) eliminate one or more tumors in the subject, (vii) improve and / or restore normal metabolism of one or more organ systems in the subject, (viii) restore and / or improve one or more aspects of cellular homeostasis and / or cellular functionality, and / or metabolic dysregulation are, or (ix) any combination thereof.

[0221] In an aspect, a disclosed anti-KRAS antibody can be used to prevent an undesired physiological change, disease, pathological condition, or disorder from occurring in the subject having cancer. In an aspect, a disclosed anti-KRAS antibody can be used to inhibit a physiological change, disease, pathological condition, or disorder, i.e., arresting its development, in the subject. In an aspect, a disclosed anti-KRAS antibody can be used to relieve a physiological change, disease, pathological condition, or disorder, i.e., causing regression of the disease, in the subject. In an aspect, a disclosed anti-KRAS antibody can be used to treat and / or prevent cancer, to prolong the survival of the subject, to prevent and / or decrease metastases, to protect the subject from metastasis, to reduce the risk of developing metastases, to increase the subject’s survivability, to increase the length of time before metastasis, to reduce the likelihood of surgical intervention, to reduce the need for administration of one or more additional therapeutic agents or regimens, toPolsinelli 24-3026-WO reduce the size of one or more tumors in the subject, to reduce the size of one or more tumors in one or more organs in the subject, to eliminate one or more tumors in the subject, to reduce and / or eliminate the prevalence of one or more genomic aberrations, to restore normal metabolism of one or more organ systems in the subject, to restore one or more aspects of cellular homeostasis, cellular functionality, and / or metabolic dysregulation in a subject, to reduce and / or inhibit aberrant angiogenesis and / or vasculogenesis in one or more tissues and / or organs of the subject, or any combination thereof.

[0222] In an aspect, a disclosed anti-KRAS antibody can be used to improve and / or can be used to enhance the quality of the subject’s life when compared to a pre-treatment level. In an aspect, a disclosed anti-KRAS antibody can be used to improve the subject’s quality of life by at least 50% when compared to the subject’s pre-treatment quality of life. In an aspect, a disclosed anti- KRAS antibody can be used to diminish and / or decrease one or more symptoms associated with and / or related to the subject’s cancer. In an aspect, a disclosed anti-KRAS antibody can be used with one or more additional therapeutic agents. In an aspect, a disclosed therapeutic agent can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof.

[0223] In an aspect, a disclosed anti-KRAS antibody can be used with one or more targeted therapies. In an aspect, a disclosed anti-KRAS antibody can be included in a disclosed pharmaceutical formulation. In an aspect, one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof can be subjected to one or more validating and / or characterizing steps and / or protocols. For example, in an aspect, validating and / or characterizing one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof can comprise measuring, ascertaining, and / or determining the purity and / or efficacy of the one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof. In an aspect, a disclosed anti-KRAS antibody can be administered to a subject having cancer in one or more routes of administration.

[0224] Disclosed herein is a nucleic acid molecule comprising a nucleic acid sequence encoding a disclosed antibody. Disclosed herein is a nucleic acid molecule comprising a nucleic acid sequence encoding a disclosed antibody targeting a mutant KRAS or a KRAS having one or more mutations. In an aspect, a disclosed KRAS can be a mutant KRAS or a KRAS having one or more mutations. In an aspect, a disclosed mutant KRAS or a KRAS having one or more mutations can comprise KRASG12A, KRASG12C, KRASG12D, KRASG12R, KRASG12S, KRASG12V, KRASG12X, KRASG13C, KRASG13D, KRASG13X, KRASQ61H, KRASQ61L, KRASQ61K, KRASQ61R, KRASQ61X,Polsinelli 24-3026-WO KRASA146T, KRASA146V, KRASA146X, or any combination thereof. In an aspect, an antibody encoded by a disclosed nucleic acid sequence can target PIGR expressed on the cell surface of a cancer cell and then an intracellular mutant KRAS.

[0225] In an aspect, a disclosed nucleic acid sequence can encode a disclosed VH or a disclosed VL. In an aspect, a disclosed nucleic acid sequence encoding a disclosed VH can be a sequence disclosed in Table 7. In an aspect, a disclosed nucleic acid sequence encoding a disclosed VL can be a sequence disclosed in Table 7. In an aspect, a disclosed nucleic acid sequence can encode a disclosed VH with a signal peptide or a disclosed VL with a signal peptide. In an aspect, a disclosed nucleic acid sequence can encode a disclosed VH with a PIGR-binding peptide (see, e.g., SEQ ID NO:8 – SEQ ID NO:10). In an aspect, a disclosed nucleic acid sequence can encode a disclosed VH with a signal peptide and with a disclosed PIGR-binding peptide (see, e.g., SEQ ID NO:14 – SEQ ID NO:16). In an aspect, a disclosed nucleic acid sequence can encode a disclosed VL with a signal peptide (see, e.g., SEQ ID NO:19) or without a signal peptide (see, e.g., SEQ ID NO:20). In an aspect, the nucleic acid sequence for a disclosed PIGR-binding peptide can be one set forth in Table 1. In an aspect, a disclosed nucleic acid sequence can encode a disclosed VH and a disclosed VL. In an aspect, a disclosed nucleic acid sequence can encode a disclosed VH CDR (see, e.g., Table 4) or a disclosed VL CDR (see, e.g., Table 2).

[0226] Disclosed herein is an expression cassette comprising a disclosed nucleic acid sequence and one or more regulatory elements. Disclosed herein is an expression cassette comprising a disclosed nucleic acid sequence and one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH or a disclosed VL, and (ii) and one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a VH sequence disclosed in Table 7, and (ii) one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a VL sequence disclosed in Table 7, and (ii) one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH with a signal peptide or a disclosed VL with a signal peptide, and (ii) one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH with a PIGR-binding peptide (see, e.g., SEQ ID NO:08 – SEQ ID NO:10), and (ii) one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH with a signal peptide and with a disclosed PIGR-binding peptide (see, e.g., SEQ ID NO:14 – SEQ ID NO:16), and (ii) one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequencePolsinelli 24-3026-WO encoding a disclosed VL with a signal peptide (see, e.g., SEQ ID NO:19) or without a signal peptide (see, e.g., SEQ ID NO:20), and (ii) one or more regulatory elements, and (ii) one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequence for a disclosed PIGR-binding peptide can be one set forth in Table 1, and (ii) one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH and a disclosed VL, and (ii) one or more regulatory elements. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH CDR (see, e.g., Table 4) or a disclosed VL CDR (see, e.g., Table 2), and (ii) one or more regulatory elements. In an aspect, a disclosed expression cassette can be incorporated into a disclosed viral vector or non-viral vector. TABLE 7 – Exemplary Nucleic Acid SequencesPolsinelli 24-3026-WOPolsinelli 24-3026-WOPolsinelli 24-3026-WO3. Other Cytosolic Targets

[0227] In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that targets a non-KRAS target. For example, a disclosed PIGR-binding peptide can be added to a VH that recognizes and binds to a cytosolic target. In an aspect, a disclosed cytosolic target can bePolsinelli 24-3026-WO produced by an epithelial cell. In an aspect, a disclosed epithelial cell can be a cell that is involved in an autoimmune disease or autoimmune condition.

[0228] In an aspect, a disclosed autoimmune disease or autoimmune condition can be psoriasis. In an aspect, a disclosed epithelial cell can be a PIGR+keratinocyte. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target Myd88. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target IL-22. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target TNF-α. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target cNF-kB. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target IL-1α. In an aspect, a disclosed PIGR- binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to a cytosolic target associated with psoriasis. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to a cytosolic target associated with psoriasis can be used in a method to treat a subject having psoriasis.

[0229] In an aspect, a disclosed autoimmune disease or autoimmune condition can be inflammatory bowel disease (IBD). In an aspect, an antibody comprising a disclosed PIGR- binding peptide can target Sting. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target Myd88. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target NLRP3. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target cNF-kB. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target IL-22.

[0230] can target IL-6. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target IL-1β. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target TNF-α. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to a cytosolic target associated with IBD. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to a cytosolic target associated with IBD can be used in a method to treat a subject having IBD.

[0231] In an aspect, a disclosed autoimmune disease or autoimmune condition can be Sjogren’s Disease or Sjogren’s syndrome. In an aspect, the targeted epithelial associated with Sjogren’s can be salivary gland epithelium. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target Myd88. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target cNF-kB. In an aspect, an antibody comprising a disclosed PIGR-binding peptide canPolsinelli 24-3026-WO target IL-7. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target TNF-α. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to a cytosolic target associated with Sjogren’s. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to a cytosolic target associated with Sjogren’s can be used in a method to treat a subject having Sjogren’s.

[0232] In an aspect, a disclosed autoimmune disease or autoimmune condition can be Celiac disease. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target Myd88. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target IL-1b. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target IL-6. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target Transglutaminase 2. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target cNF-kB. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to a cytosolic target associated with Celiac disease. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to a cytosolic target associated with Celiac disease can be used in a method to treat a subject having Celiac disease.

[0233] In an aspect, a disclosed autoimmune disease or autoimmune condition can be autoimmune gastritis. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target IL-33. In an aspect, an antibody comprising a disclosed PIGR-binding peptide can target IL-11. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to a cytosolic target associated with autoimmune gastritis. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to a cytosolic target associated with autoimmune gastritis can be used in a method to treat a subject having autoimmune gastritis. 4. Other Oncogenic Targets

[0234] In an aspect, a disclosed PIGR-binding peptide can be added to a VH of an antibody that targets a mutated oncogene or an oncogenic driver. For example, a disclosed PIGR-binding peptide can be added to a VH that recognizes and binds to a mutated oncogene or an oncogenic driver. In an aspect, a disclosed cytosolic target can be produced by an epithelial cell including epithelial cells associated with cancer.Polsinelli 24-3026-WO

[0235] In an aspect, a disclosed cytosolic target can be produced by a cell associated with cancer. In an aspect, a disclosed cytosolic target can be produced by a cancer cell. In an aspect, a disclosed cancer cell can express PIK3CAH1047R. In an aspect, PIK3CAH1047Rcan be expressed in breast cancer. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to PIK3CAH1047Rassociated with cancer (including breast cancer). In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to PIK3CAH1047Rcan be used in a method to treat a subject having cancer (including breast cancer).

[0236] In an aspect, a disclosed cytosolic target can be produced by a cell associated with cancer. In an aspect, a disclosed cytosolic target can be produced by a cancer cell. In an aspect, a disclosed cancer cell can express PIK3CAE545K. In an aspect, PIK3CAE545Kcan be expressed in cancer including breast cancer, prostate cancer, cervical cancer, non-small cell lung cancer, colorectal cancer, or any combination thereof. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to PIK3CAE545Kassociated with cancer including breast cancer, prostate cancer, cervical cancer, non-small cell lung cancer, or colorectal cancer. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to PIK3CAE545Kcan be used in a method to treat a subject having cancer including breast cancer, prostate cancer, cervical cancer, non-small cell lung cancer, or colorectal cancer).

[0237] In an aspect, a disclosed cytosolic target can be produced by a cell associated with cancer. In an aspect, a disclosed cytosolic target can be produced by a cancer cell. In an aspect, a disclosed cancer cell can express BRAFV600E. In an aspect, BRAFVV600Ecan be expressed in various cancers. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to BRAFVV600Eassociated with cancer. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to BRAFVV600Ecan be used in a method to treat a subject having cancer.

[0238] In an aspect, a disclosed cytosolic target can be produced by an epithelial cell associated with cancer. In an aspect, a disclosed cytosolic target can be produced by a cancerous epithelial cell. In an aspect, a disclosed cancerous epithelial cell can express BRAFV600E. In an aspect, BRAFVV600Ecan be expressed in various epithelial cancers. In an aspect, a disclosed PIGR- binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, aPolsinelli 24-3026-WO disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to BRAFV600Eassociated with cancer. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to BRAFVV600Ecan be used in a method to treat a subject having cancer.

[0239] In an aspect, a disclosed cytosolic target can be produced by a cell associated with cancer. In an aspect, a disclosed cytosolic target can be produced by a cancer cell. In an aspect, a disclosed cancer cell can express TP53R248Q. In an aspect, TP53R248Qcan be expressed in cancer including prostate cancer, bladder cancer, pancreatic cancer, head and neck cancer, esophageal cancer, endometrial cancer, stomach cancer, cervical cancer, or any combination thereof. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to TP53R248Qassociated with cancer including prostate cancer, bladder cancer, pancreatic cancer, head and neck cancer, esophageal cancer, endometrial cancer, stomach cancer, cervical cancer, or any combination thereof. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to TP53R248Qcan be used in a method to treat a subject having prostate cancer, bladder cancer, pancreatic cancer, head and neck cancer, esophageal cancer, endometrial cancer, stomach cancer, cervical cancer, or any combination thereof.

[0240] In an aspect, a disclosed cytosolic target can be produced by a cell associated with cancer. In an aspect, a disclosed cytosolic target can be produced by a cancer cell. In an aspect, a disclosed cancer cell can express TP53R273H. In an aspect, TP53R273Hcan be expressed in cancer including breast cancer, colon cancer, head and neck cancer, ovarian cancer, or any combination thereof. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to an antibody that recognizes and binds to TP53R273Hassociated with cancer including breast cancer, colon cancer, head and neck cancer, ovarian cancer, or any combination thereof. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to TP53R273Hcan be used in a method to treat a subject having breast cancer, colon cancer, head and neck cancer, ovarian cancer, or any combination thereof.

[0241] In an aspect, a disclosed cytosolic target can be produced by a cell associated with cancer. In an aspect, a disclosed cytosolic target can be produced by a cancer cell. In an aspect, a disclosed cancer cell can express NRASQ61K. In an aspect, NRASQ61Kcan be expressed in cancer cells. In an aspect, a disclosed PIGR-binding peptide can comprise a PIGR-binding peptide provided in Table 1. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 can be linked to anPolsinelli 24-3026-WO antibody that recognizes and binds to NRASQ61Kassociated with cancer. In an aspect, a disclosed PIGR-binding peptide provided in Table 1 linked to an antibody that recognizes and binds to NRASQ61Kcan be used in a method to treat a subject having cancer.

[0242] In an aspect, an antibody directed at a disclosed cytosolic target can be formulated into a pharmaceutical formulation. 5. Vectors & Plasmids

[0243] Disclosed herein is a vector comprising a disclosed nucleic acid molecule or a disclosed nucleic acid sequence. Disclosed herein is a vector comprising one or more disclosed nucleic acid molecules or one or more disclosed nucleic acid sequences. Nucleic acid molecules and nucleic acid sequences are disclosed supra, for example, in connection with the disclosure of antibodies. Disclosed herein is a vector comprising one or more nucleic acid molecules or one or more nucleic acid sequences set forth in Table 7. Disclosed herein is a vector comprising a nucleic acid molecule or a nucleic acid sequence encoding a disclosed anti-KRAS antibody or a component thereof (e.g., VH or VL or PIGR-binding peptide). Disclosed herein is a vector comprising a nucleic acid molecule or a nucleic acid sequence encoding a VH set forth in Table 5 or Table 6. Disclosed herein is a vector comprising a nucleic acid molecule or a nucleic acid sequence encoding a VL set forth in Table 3. Disclosed herein is a vector comprising one or more nucleic acid sequences as set forth in any one of SEQ ID NO:08 – SEQ ID NO:10 and in any one of SEQ ID NO:19 – SEQ ID NO:20.

[0244] Disclosed herein is a vector comprising a nucleic acid molecule or nucleic acid sequence that encodes a disclosed antibody. Disclosed herein is a plasmid comprising a disclosed nucleic acid molecule or a disclosed nucleic acid sequence. Disclosed herein is a plasmid comprising one or more disclosed nucleic acid molecules or one or more disclosed nucleic acid sequences. Nucleic acid molecules and nucleic acid sequences are disclosed supra, for example, in connection with the disclosure of antibodies. Disclosed herein is a plasmid comprising one or more nucleic acid molecules or one or more nucleic acid sequences set forth in Table 7. Disclosed herein is a plasmid comprising a nucleic acid molecule or a nucleic acid sequence encoding a disclosed anti-KRAS antibody or a component thereof (e.g., VH or VL or PIGR-binding peptide). Disclosed herein is a plasmid comprising a nucleic acid molecule or a nucleic acid sequence encoding a VH set forth in Table 5 or Table 6. Disclosed herein is a plasmid comprising a nucleic acid molecule or a nucleic acid sequence encoding a VL set forth in Table 3. Disclosed herein is a plasmid comprising one or more nucleic acid sequences as set forth in any one of SEQ ID NO:08 – SEQ ID NO:10 and in any one of SEQ ID NO:19 – SEQ ID NO:20. Disclosed herein is a plasmid comprising a nucleic acid molecule or nucleic acid sequence that encodes a disclosed antibody.Polsinelli 24-3026-WO

[0245] Vectors and plasmids are known to the skilled person in the art.

[0246] In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising a disclosed nucleic acid sequence and one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising a disclosed nucleic acid sequence and one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH or a disclosed VL, and (ii) and one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a VH sequence disclosed in Table 7, and (ii) one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a VL sequence disclosed in Table 7, and (ii) one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH with a signal peptide or a disclosed VL with a signal peptide, and (ii) one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH with a PIGR-binding peptide (see, e.g., SEQ ID NO:08 – SEQ ID NO:10), and (ii) one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH with a signal peptide and with a disclosed PIGR-binding peptide (see, e.g., SEQ ID NO:14 – SEQ ID NO:16), and (ii) one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VL with a signal peptide (see, e.g., SEQ ID NO:19) or without a signal peptide (see, e.g., SEQ ID NO:20), and (ii) one or more regulatory elements, and (ii) one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence for a disclosed PIGR-binding peptide can be one set forth in Table 1, and (ii) one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH and a disclosed VL, and (ii) one or more regulatory elements. In an aspect, a disclosed vector or a disclosed plasmid can comprise an expression cassette comprising (i) a disclosed nucleic acid sequence encoding a disclosed VH CDR (see, e.g., Table 4) or a disclosed VL CDR (see, e.g., Table 2), and (ii) one or more regulatory elements.Polsinelli 24-3026-WO

[0247] In an aspect, a disclosed vector or a disclosed plasmid can be used to generate any disclosed anti-KRAS antibody or any other antibody directed at a cytosolic target or oncogenic target. In an aspect, a disclosed vector or a disclosed plasmid can be used to validate any disclosed anti-KRAS antibody or any other antibody directed at a cytosolic target or oncogenic target.

[0248] Disclosed herein is a vector comprising a disclosed nucleic acid molecule or a disclosed nucleic acid sequence. Disclosed herein is a vector comprising one or more disclosed nucleic acid molecules or one or more disclosed nucleic acid sequences. Nucleic acid molecules and nucleic acid sequences are disclosed supra, for example, in connection with the disclosure of antibodies.

[0249] Disclosed herein is a vector comprising one or more nucleic acid molecules or one or more nucleic acid sequences set forth in Table 7. Disclosed herein is a vector comprising a nucleic acid molecule or a nucleic acid sequence encoding a disclosed anti-KRAS antibody or a component thereof (e.g., VH or VL or PIGR-binding peptide). Disclosed herein is a vector comprising a nucleic acid molecule or a nucleic acid sequence encoding a VH set forth in Table 5 or Table 6. Disclosed herein is a vector comprising a nucleic acid molecule or a nucleic acid sequence encoding a VL set forth in Table 3. Disclosed herein is a vector comprising a nucleic acid molecule or nucleic acid sequence that encodes a disclosed antibody.

[0250] In an aspect, non-viral vectors are known to the skilled person in the art. In an aspect, a disclosed non-viral vector can be a polymer-based vector, a peptide-based vector, a lipid nanoparticle, a solid lipid nanoparticle, or a cationic lipid-based vector. In an aspect, a disclosed vector can comprise exosomes, extracellular vesicles, and virus like particles. In an aspect, a disclosed viral vector can be an adenovirus vector, an AAV vector, a herpes simplex virus vector, a retrovirus vector, a lentivirus vector, and alphavirus vector, a Flavivirus vector, a rhabdovirus vector, a measles virus vector, a Newcastle disease viral vector, a poxvirus vector, or a picornavirus vector. .In an aspect, a disclosed recombinant viral vector can be a recombinant adenovirus vector, a recombinant AAV vector, a recombinant herpes simplex virus vector, a recombinant retrovirus vector, a recombinant lentivirus vector, and a recombinant alphavirus vector, a recombinant Flavivirus vector, a recombinant rhabdovirus vector, a recombinant measles virus vector, a recombinant Newcastle disease viral vector, a recombinant poxvirus vector, or a recombinant picornavirus vector.

[0251] In an aspect, a disclosed vector or a disclosed plasmid can comprise one or more ITRs. In an aspect of a disclosed vector, a disclosed nucleic acid molecule or a disclosed expression cassette can be flanked by one or more AAV inverted terminal repeat (ITR) sequences. In an aspect, disclosed ITRs can be ITRs from any disclosed AAV. In an aspect, disclosed AAV ITRs can be ITRs from AAV1, AAV2, AAV3 (including 3a and 3b), AAV4, AAV5, AAV6, AAV7, AAV8,Polsinelli 24-3026-WO AAVrh8, AAV9, AAV10, AAVrh10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV17, AAV18, AAV19, AAV20, AAV21, AAV22, AAV23, AAV24-30, AAV31,AAV37, AAV40, AAV41, AdHu2, AdHu 3, AdHu4, AdHu24, AdHu26, AdHu34, AdHu35, AdHu36, AdHu37, AdHu41, AdHu48, AdHu49, AdHu50, AdC6, AdC7, AdC69, AAVrh39, AAVrh43, AAVcy.7 as well as bovine AAV, caprine AAV, canine AAV, equine AAV, ovine AAV, avian AAV, primate AAV, non-primate AAV, and any other virus classified by the International Committee on Taxonomy of Viruses (ICTV) as an AAV. In an aspect, disclosed AAV ITRs can be ITRs from AAV-DJ, AAV-DJ / 8, AAV-MG, AAV2.7m8, AAV2-QuadYF, AAV-HAE1, AAV- HAE2, AAVM41, AAV-BI30, AAV-1829, AAV2 Y / F, AAV2 T / V, AAV2i8, AAV2.5, AAV9.45, AAV9.61, AAV-B1, AAV-AS, AAV9.45A-String (e.g., AAV9.45-AS), AAV9.45Angiopep, AAV9.47-Angiopep, and AAV9.47-AS, AAV-PHP.B, AAV-PHP.eB, AAV- PHP.S, AAV-F, AAVcc.47, and AAVcc.81

[0252] In an aspect, a disclosed vector or a disclosed plasmid can comprise stuffer nucleic acid.

[0253] In an aspect, a disclosed vector or a disclosed plasmid can comprise one or more nuclear localization signals (NLS). NLS are known to the skilled person in the art. In an aspect, a disclosed NLS can comprise any NLS known to the art. As known to the art (see, e.g., Lu J, et al. (2021) Cell Commun Signal.19:60, which is incorporated herein by reference for its teachings of NLS), nuclear localization signals (NLS) are generally short peptides that act as a signal fragment that mediates the transport of proteins from the cytoplasm into the nucleus.

[0254] In an aspect, a disclosed vector can further comprise one or more nuclear retention elements (NRE). NRE are known to the skilled person in the art. In an aspect, a disclosed NRE can comprise SIRLOIN or BORG.

[0255] In an aspect, a disclosed vector can comprise one or more promoters operably linked to a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence. In an aspect of a disclosed vector, a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence can be operably linked to one or more transcription regulatory elements. In an aspect, the one or more transcription regulatory elements (e.g., Woodchuck Hepatitis Virus (WHV) Posttranscriptional Regulator Element (WPRE), triplex from MALAT1, the PRE of Hepatitis B virus (HPRE), and an iron response element) can increase the transcription and / or expression of a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence. In an aspect, a disclosed promoter can be positioned 5’ (upstream) or 3’ (downstream) of a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence under its control. The distance between a disclosed promoter and a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence can be approximately the same as the distance between that promoter and to the disclosed nucleic acid molecule and / orPolsinelli 24-3026-WO a disclosed nucleic acid sequence under its control. As is known in the art, variation in this distance can be accommodated without loss of promoter function.

[0256] In an aspect, a disclosed vector or a disclosed plasmid can be formulated in a pharmaceutical formulation. In an aspect, a disclosed vector or a disclosed plasmid can be formulated for administration via one or more routes. Such methods are well known to those skilled in the art and include, but are not limited to, the following routes: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intraaural administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can also include hepatic intra-arterial administration or administration through the hepatic portal vein (HPV). Administration of a disclosed therapeutic agent, a disclosed pharmaceutical composition, or a combination thereof can comprise administration directly into the CNS (e.g., intraparenchymal, intracerebroventricular, intrathecal cisternal, intrathecal (lumbar), deep gray matter delivery, convection-enhanced delivery to deep gray matter) or the PNS. Administration can be continuous or intermittent. Administration can comprise administering a viral vector and / or generated optimized viral vector. Administration of a disclosed vector can be continuous or intermittent. 6. Pharmaceutical Formulations

[0257] Disclosed herein is a pharmaceutical formulation comprising one or more disclosed anti- KRAS antibody, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising one or more anti-KRAS antibody comprising an IgG backbone, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising an anti-KRAS antibody comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) binding peptide, wherein the antibody recognizes the GTP-bound active form of KRAS, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising an antibody recognizing the GTP-bound active conformation of mutant KRAS comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) binding peptide, wherein the antibody recognizes the GTP-bound active form of KRAS, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising one or more anti-KRAS antibodies comprising an IgGPolsinelli 24-3026-WO backbone and one or more polymeric immunoglobulin receptor (PIGR) binding peptide, wherein the one or more antibodies recognize the GTP-bound active form of KRAS, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising one or more anti-KRAS antibodies recognizing the GTP-bound active conformation of mutant KRAS comprising an IgG backbone and one or more polymeric immunoglobulin receptor (PIGR) binding peptide, wherein the one or more antibodies recognize the GTP-bound active form of KRAS, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising one or more disclosed nucleic acid molecules and one or more pharmaceutically acceptable carriers and / or excipients.

[0258] Disclosed herein is a pharmaceutical formulation comprising one or more disclosed nucleic acid molecules set forth in Table 7 and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a disclosed vector and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising one or more nucleic acid sequences as set forth in any one of SEQ ID NO:08 – SEQ ID NO:10 and in any one of SEQ ID NO:19 – SEQ ID NO:20, and one or more pharmaceutically acceptable carriers and / or excipients.

[0259] In an aspect, a disclosed pharmaceutical formulation can be administered to a subject in need thereof. In an aspect, a disclosed pharmaceutical formulation can be formulated for administration and / or can be administered via one or more routes. Such methods are well known to those skilled in the art and include, but are not limited to, the following routes: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intraaural administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can also include hepatic intra- arterial administration or administration through the hepatic portal vein (HPV). Administration of a disclosed pharmaceutical formulation can comprise administration directly into the CNS (e.g., intraparenchymal, intracerebroventricular, intrathecal cisternal, intrathecal (lumbar), deep gray matter delivery, convection-enhanced delivery to deep gray matter) or the PNS. Administration can be continuous or intermittent. Administration of a disclosed pharmaceutical formulation can comprise intra-tumoral administration.Polsinelli 24-3026-WO

[0260] In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-KRAS antibody can be used in a disclosed method. In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-KRAS antibody can be used in a disclosed method of treating a subject having cancer.

[0261] In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed anti-KRAS antibody comprising an IgG backbone. In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-KRAS antibody comprising an IgG backbone can be used in a disclosed method of treating a subject having cancer.

[0262] In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-KRAS antibody comprising an IgG backbone can be used in a method of treating a subject having pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, bladder adenocarcinoma, endometroid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, colorectal adenocarcinoma, or pancreatic carcinoma.

[0263] In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-KRAS antibody comprising an IgG backbone in a method of treating a subject having a cancer characterized by one or more KRAS mutations and / or caused by one or more KRAS mutations.

[0264] In an aspect, a disclosed pharmaceutical formulation comprising a disclosed anti-KRAS antibody comprising an IgG backbone can induce PIGR mediated transcytosis in one or more cells including, for example, one or more cancer cells and / or one or more tumor cells.

[0265] In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed cytosolic target associated with an autoimmune disease or autoimmune condition (such as, for example, Myd88, IL-22, TNF-α, cNF-kB, IL-1α, or any combination thereof). In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed cytosolic target associated with inflammatory bowel disease (IBD) (such as, for example, Sting, Myd88, NLRP3, cNF-kB, IL-22, IL-6, IL-1β, TNF-α, or any combination thereof). In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed cytosolic target associated with Sjogren’s Disease or Sjogren’s syndrome (e.g., Myd88, cNF-kB, IL-7, TNF-α, or any combination thereof). In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed cytosolic target associated with Celiac disease (e.g., Myd88, IL-1b, IL-6, Transglutaminase 2, cNF-kB, or any combination thereof. In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed cytosolic target associated with autoimmune gastritis (e.g., IL-33, and / or IL-11). In an aspect, a disclosed antibody targeting an autoimmune or autoimmunePolsinelli 24-3026-WO condition can comprise a disclosed 20-mer PIGR-binding peptide, a disclosed 16-mer PIGR- binding peptide, or a disclosed 12-mer PIGR-binding peptide (see, e.g., those in Table 1).

[0266] In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed oncogenic target associated with expression of PIK3CAH1047R. In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed oncogenic target associated with expression of PIK3CAE545K. In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed oncogenic target associated with expression of BRAFV600E. In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed oncogenic target associated with expression of TP53R248Q. In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed oncogenic target associated with expression of TP53R273H. In an aspect, a disclosed pharmaceutical formulation can comprise a disclosed antibody targeting a disclosed oncogenic target associated with expression of NRASQ61K. In an aspect, a disclosed antibody targeting an oncogenic can comprise a disclosed 20-mer PIGR- binding peptide, a disclosed 16-mer PIGR-binding peptide, or a disclosed 12-mer PIGR-binding peptide (see, e.g., those in Table 1).

[0267] In an aspect, a disclosed pharmaceutical formulation can be used to (i) prevent and / or decrease the risk of developing metastases, (ii) prolong the survival of the subject, (iii) enhance and / or improve the subject’s quality of life, (iv) reduce and / or minimize the likelihood of surgical intervention, (v) reduce and / or decrease the size of one or more tumors in the subject, (vi) eliminate one or more tumors in the subject, (vii) improve and / or restore normal metabolism of one or more organ systems in the subject, (viii) restore and / or improve one or more aspects of cellular homeostasis and / or cellular functionality, and / or metabolic dysregulation are, or (ix) any combination thereof.

[0268] In an aspect, a disclosed pharmaceutical formulation can be used with one or more additional therapeutic agents. In an aspect, a disclosed pharmaceutical formulation comprising can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof. In an aspect, a disclosed pharmaceutical formulation can be used with one or more targeted therapies.

[0269] In an aspect, a disclosed pharmaceutical formulation can be used to treat and / or prevent cancer, to prolong the survival of the subject, to prevent and / or decrease metastases, to protect the subject from metastasis, to reduce the risk of developing metastases, to increase the subject’s survivability, to increase the length of time before metastasis, to reduce the likelihood of surgicalPolsinelli 24-3026-WO intervention, to reduce the need for administration of one or more additional therapeutic agents or regimens, to reduce the size of one or more tumors in the subject, to reduce the size of one or more tumors in one or more organs in the subject, to eliminate one or more tumors in the subject, to reduce and / or eliminate the prevalence of one or more genomic aberrations, to restore normal metabolism of one or more organ systems in the subject, to restore one or more aspects of cellular homeostasis, cellular functionality, and / or metabolic dysregulation in a subject, to reduce and / or inhibit aberrant angiogenesis and / or vasculogenesis in one or more tissues and / or organs of the subject, or any combination thereof.

[0270] In an aspect, a disclosed pharmaceutical formulation can be used to improve and / or can be used to enhance the quality of the subject’s life when compared to a pre-treatment level. In an aspect, a disclosed pharmaceutical formulation can be used to improve the subject’s quality of life by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% when compared to the subject’s pre-treatment quality of life.

[0271] In an aspect, a disclosed pharmaceutical formulation can be used to diminish and / or decrease one or more symptoms associated with and / or related to the subject’s cancer. In an aspect, a disclosed pharmaceutical formulation can be used to diminish and / or decrease one or more symptoms associated with and / or related to the subject’s cancer by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% when compared to the subject’s pre-treatment symptoms.

[0272] In an aspect, a disclosed pharmaceutical formulation can be used to prevent an undesired physiological change, disease, pathological condition, or disorder from occurring in the subject having cancer. In an aspect, a disclosed pharmaceutical formulation can be used to inhibit a physiological change, disease, pathological condition, or disorder, i.e., arresting its development, in the subject. In an aspect, a disclosed pharmaceutical formulation can be used to relieve a physiological change, disease, pathological condition, or disorder, i.e., causing regression of the disease, in the subject.

[0273] In an aspect, one or more disclosed pharmaceutical formulations can be subjected to one or more validating and / or characterizing steps and / or protocols. For example, in an aspect, validating and / or characterizing one or more disclosed pharmaceutical formulations can comprise measuring, ascertaining, and / or determining the purity and / or efficacy of the one or more disclosed pharmaceutical formulations. 7. KitsPolsinelli 24-3026-WO

[0274] Disclosed herein is a kit comprising one or more disclosed anti-KRAS antibodies. Disclosed herein is a kit comprising one or more disclosed anti-KRAS antibodies and one or more targeted therapies. Disclosed herein is a kit comprising on Disclosed herein is a kit comprising one or more disclosed anti-KRAS, wherein the one or more disclosed anti-KRAS antibodies are used to treat a subject having one or more cancers. Disclosed herein is a kit comprising one or more disclosed anti-KRAS antibodies and one or more targeted therapies, wherein the one or more disclosed anti-KRAS antibodies and the targeted therapies are used to treat a subject having one or more cancers.

[0275] Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-KRAS antibodies. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-KRAS antibodies and one or more targeted therapies. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-KRAS antibodies, wherein the pharmaceutical formulation comprising one or more disclosed anti-KRAS are used to treat a subject having one or more cancers. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-KRAS antibodies and one or more targeted therapies, wherein the pharmaceutical formulation comprising one or more disclosed anti-KRAS antibodies and the targeted therapies are used to treat a subject having one or more cancers.

[0276] Disclosed herein is a kit comprising one or more disclosed anti-KRAS antibodies for one or more treatment cycles. Disclosed herein is a kit comprising one or more disclosed anti-KRAS antibodies, wherein the one or more disclosed anti-KRAS antibodies are used to treat a subject having one or more cancers for one or more treatment cycles. Disclosed herein is a kit comprising one or more disclosed anti-KRAS antibodies, wherein the one or more disclosed anti-KRAS antibodies are used to treat a subject having cancer or metastatic cancer for one or more treatment cycles. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-KRAS antibodies for one or more treatment cycles. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti- KRAS antibodies, wherein the pharmaceutical formulation comprising one or more disclosed anti- KRAS antibodies are used to treat a subject having one or more cancers for one or more treatment cycles.

[0277] Disclosed herein is a kit comprising one or more disclosed anti-KRAS antibodies and one or more targeted therapies for one or more treatment cycles. Disclosed herein is a kit comprising one or more disclosed anti-KRAS antibodies and one or more targeted therapies, wherein the one or more disclosed anti-KRAS antibodies and the targeted therapies are used to treat a subjectPolsinelli 24-3026-WO having one or more cancers for one or more treatment cycles. Disclosed herein is a kit comprising one or more disclosed anti-KRAS antibodies and one or more targeted therapies, wherein the one or more disclosed anti-KRAS antibodies and the targeted therapies are used to treat a subject having cancer or metastatic cancer for one or more treatment cycles. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti-KRAS antibodies and one or more targeted therapies for one or more treatment cycles. Disclosed herein is a kit comprising a disclosed pharmaceutical formulation comprising one or more disclosed anti- KRAS antibodies one or more targeted therapies, wherein the pharmaceutical formulation comprising one or more disclosed anti-KRAS antibodies and the targeted therapies are used to treat a subject having one or more cancers for one or more treatment cycles.

[0278] In an aspect, by using a disclosed kit, (i) the risk of developing metastases can be prevented and / or decreased; (ii) the survival of the subject can be prolonged; (iii) the subject’s quality of life can be enhanced and / or improved; (iv) the likelihood of surgical intervention can be reduced and / or minimized; (v) preventing and / or delaying recurrence of the cancer; (vi) the size of one or more tumors in the subject can be reduced and / or decreased; (vii) one or more tumors in the subject can be eliminated; (viii) extending and / or prolonging disease-free or tumor-free survival time; (ix) increasing and / or lengthening overall survival time; (x) reducing and / or minimizing the frequency of treatment; (xi) relieving and / or ameliorating one or more symptoms of the cancer; (xii) reducing and / or decreasing tumor burden, (ix) preventing and / or facilitating surgical intervention; (xiii) normal metabolism of one or more organ systems in the subject can be improved and / or restored, (xiv) one or more aspects of cellular homeostasis and / or cellular functionality, and / or metabolic dysregulation can be restored and / or improved, or (xv) any combination thereof.

[0279] In an aspect, a disclosed kit can comprise one or more additional and / or therapeutic agents. “Agents” and “Therapeutic Agents” are known to the art and are described herein. In an aspect, a disclosed agent or a disclosed therapeutic agent can comprise one or more monoclonal antibodies, one or more antibody-drug conjugates, one or more kinase inhibitors, one or more CDK4 and / or CDK6 inhibitors, one or more mTOR inhibitors, one or more ADK inhibitors, one or more PI3K inhibitors, one or more PARP inhibitors, or any combination thereof.

[0280] In an aspect, a disclosed kit can comprise a disclosed chemotherapeutic agent. In an aspect, a disclosed chemotherapeutic agent can comprise anthracycline-based chemotherapy or can comprise non-anthracycline-based chemotherapy. In an aspect, a disclosed chemotherapeutic agent can comprise oxaliplatin, doxorubicin, daunorubicin, docetaxel, mitoxanthrone, paclitaxel, digitoxin, digoxin, septacidin, 5-fluorouracil and epirubicin, doxorubicin and cyclophosphamide, epirubicin and cyclophosphamide, docetaxel and carboplatin, or any combination thereof. In anPolsinelli 24-3026-WO aspect, a disclosed chemotherapeutic agent can be formulated as a polymeric micelle formulation, a liposomal formulation, a dendrimer formulation, a polymer-based nanoparticle formulation, a silica-based nanoparticle formulation, a nanoscale coordination polymer formulation, an inorganic nanoparticle formulation, or any combination thereof.

[0281] In an aspect, a disclosed kit can comprise targeted immunotherapy agent (e.g., fam- trastuzumab-deruxtecan-nxki; trastuzumab; Herceptin Hylecta (injectable Herceptin); Herceptin biosimilars (e.g., Herzuma, Kanjinti, Ogivri, Ontruzant, and Trazimera); ado-trastuzumab emtansine; margetuximab-cmkb; pertuzumab, trastuzumab, and hyaluronidase-zzxf; pertuzumab; sacituzumab govitecan-hziy; or any combination thereof).

[0282] In an aspect, a disclosed kit can be used to validate and / or characterize (i) one or more disclosed anti-KRAS antibodies having an IgG backbone and / or a pharmaceutical formulation thereof. In an aspect, validating and / or characterizing can comprise measuring, ascertaining, and / or determining the purity and / or efficacy of the one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof.

[0283] In an aspect, a disclosed kit can comprise one or more disclosed anti-KRAS antibodies formulated as a capsule and / or tablets for oral administration. In an aspect, a disclosed kit can comprise one or more disclosed anti-KRAS antibodies formulated as a solution for intravenous administration.

[0284] In an aspect, a disclosed kit can comprise one or more targeted therapies. In an aspect, a disclosed targeted therapy can be a commercially available targeted therapy. In an aspect, a disclosed targeted therapy can be an experimental targeted therapy. Targeted therapies are discussed supra.

[0285] In an aspect, a disclosed kit can comprise at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose (such as, for example, treating a subject diagnosed with or suspected of having a disease or disorder such as cancer). Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0286] In an aspect, a disclosed kit for use in a disclosed method can comprise one or more containers holding a disclosed treatment regimen, a disclosed anti-KRAS antibody, a disclosed targeted therapy, a disclosed pharmaceutical formulation, a disclosed anti-chemokine, a disclosedPolsinelli 24-3026-WO anti-cancer agent, a disclosed chemotherapeutic agent, or a combination thereof, and a label or package insert with instructions for use. In an aspect, suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The containers can be formed from a variety of materials such as glass or plastic. The container can hold one or more disclosed anti-KRAS antibodies, one or more disclosed pharmaceutical formulations comprising one or more disclosed anti-KRAS antibodies, or any combination thereof, and can have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert can indicate one or more disclosed anti-KRAS antibodies, disclosed pharmaceutical formulations, or any combination thereof can be used for treating, preventing, inhibiting, and / or ameliorating a disease or disorder or complications and / or symptoms associated with cancer or metastatic cancer (e.g., cancer or breast cancer). A kit can comprise additional components necessary for administration such as, for example, other buffers, diluents, filters, needles, and syringes. D. Methods

[0287] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed anti- KRAS antibody. Disclosed herein is a method for treating a subject having cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti-KRAS antibodies or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies. Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more disclosed anti-KRAS antibodies. Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation comprising one or more disclosed anti-KRAS antibodies. Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation comprising a disclosed anti-KRAS antibody. Disclosed herein is a method for treating cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti- KRAS antibodies or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies. Disclosed herein is a method for reducing metastases in a subject having cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti-KRASPolsinelli 24-3026-WO antibodies or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies, wherein the subject demonstrates a tumor response and / or molecular response to treatment regimen, and wherein metastases are prevented and / or decreased. Disclosed herein is a method for reducing metastases in a subject having, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more anti-KRAS antibodies, and a therapeutically effective amount of one or more targeted therapies, wherein the subject demonstrates a tumor response and / or molecular response to treatment regimen, and wherein metastases are prevented and / or decreased.

[0288] Disclosed herein is a method of treating a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed antibody targeting expression of cNF-kB, IL-11, IL-1b, IL-1α, IL-1β, IL-22, IL-33, IL-6, IL-7, Myd88, NLRP3, Sting, TNF-α, or Transglutaminase 2 by epithelial cells associated with autoimmune diseases or conditions. Disclosed herein is a method for treating a subject, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more disclosed antibodies targeting expression of cNF-kB, IL-11, IL- 1b, IL-1α, IL-1β, IL-22, IL-33, IL-6, IL-7, Myd88, NLRP3, Sting, TNF-α, or Transglutaminase 2 by epithelial cells associated with autoimmune diseases or conditions or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies. Disclosed herein is a method of treating a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more disclosed antibodies targeting expression of cNF-kB, IL-11, IL-1b, IL-1α, IL-1β, IL-22, IL-33, IL-6, IL-7, Myd88, NLRP3, Sting, TNF-α, or Transglutaminase 2 by epithelial cells associated with autoimmune diseases or conditions. Disclosed herein is a method of treating a subject r, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation comprising one or more disclosed antibodies targeting expression of cNF-kB, IL-11, IL-1b, IL-1α, IL-1β, IL-22, IL-33, IL-6, IL-7, Myd88, NLRP3, Sting, TNF-α, or Transglutaminase 2 by epithelial cells associated with autoimmune diseases or conditions. Disclosed herein is a method of treating a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation comprising a disclosed antibody targeting expression of cNF-kB, IL-11, IL-1b, IL-1α, IL-1β, IL-22, IL-33, IL-6, IL-7, Myd88, NLRP3, Sting, TNF-α, or Transglutaminase 2 by epithelial cells associated with autoimmune diseases or conditions. Disclosed herein is a method for treating an autoimmune disease or autoimmune condition, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeuticallyPolsinelli 24-3026-WO effective amount of one or more disclosed antibodies targeting expression of cNF-kB, IL-11, IL- 1b, IL-1α, IL-1β, IL-22, IL-33, IL-6, IL-7, Myd88, NLRP3, Sting, TNF-α, or Transglutaminase 2 by epithelial cells associated with autoimmune diseases or conditions or a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies. In an aspect, all disclosed antibodies comprise a disclosed PIGR-binding peptide (see, e.g., Table 1).

[0289] Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed antibody targeting expression of PIK3CAH1047R, PIK3CAE545K, BRAFV600E, TP53R248Q, TP53R273H, or NRASQ61K. Disclosed herein is a method for treating a subject having cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more antibodies targeting expression of PIK3CAH1047R, PIK3CAE545K, BRAFV600E, TP53R248Q, TP53R273H, or NRASQ61Kor a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies. Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more disclosed antibodies targeting expression of PIK3CAH1047R, PIK3CAE545K, BRAFV600E, TP53R248Q, TP53R273H, or NRASQ61K. Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation comprising one or more disclosed antibodies targeting expression of PIK3CAH1047R, PIK3CAE545K, BRAFV600E, TP53R248Q, TP53R273H, or NRASQ61K. Disclosed herein is a method of treating a subject having cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation comprising a disclosed antibody targeting expression of PIK3CAH1047R, PIK3CAE545K, BRAFV600E, TP53R248Q, TP53R273H, or NRASQ61K. Disclosed herein is a method for treating cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more antibodies targeting expression of PIK3CAH1047R, PIK3CAE545K, BRAFV600E, TP53R248Q, TP53R273H, or NRASQ61Kor a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies. Disclosed herein is a method for reducing metastases in a subject having cancer, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more antibodies targeting expression of PIK3CAH1047R, PIK3CAE545K, BRAFV600E, TP53R248Q, TP53R273H, or NRASQ61Kor a pharmaceutical formulation thereof, and a therapeutically effective amount of one or more targeted therapies, wherein the subject demonstrates a tumor response and / or molecular response to treatment regimen, andPolsinelli 24-3026-WO wherein metastases are prevented and / or decreased. Disclosed herein is a method for reducing metastases in a subject having, the method comprising administering to a subject in need thereof a treatment regimen comprising a therapeutically effective amount of one or more antibodies targeting expression of PIK3CAH1047R, PIK3CAE545K, BRAFV600E, TP53R248Q, TP53R273H, or NRASQ61K, and a therapeutically effective amount of one or more targeted therapies, wherein the subject demonstrates a tumor response and / or molecular response to treatment regimen, and wherein metastases are prevented and / or decreased.

[0290] In an aspect, a disclosed cancer can be a KRAS mutation driven cancer. In an aspect, a disclosed cancer can be characterized as a mutant KRAS related and / or mutant KRAS adjacent cancer. KRAS mutations are common in a variety of cancers. For example, a disclosed mutant KRAS can comprise KRASG12A, KRASG12C, KRASG12D, KRASG12R, KRASG12S, KRASG12V, KRASG12X, KRASG13C, KRASG13D, KRASG13X, KRASQ61H, KRASQ61L, KRASQ61K, KRASQ61R, KRASQ61X, KRASA146T, KRASA146V, KRASA146X, or any combination thereof. In an aspect, a disclosed cancer can be characterized by cells expressing PIGR.

[0291] In an aspect, cancer can be pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, bladder adenocarcinoma, endometroid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, colorectal adenocarcinoma, or pancreatic carcinoma.

[0292] In an aspect, following the administering step, PIGR mediated transcytosis can be induced.

[0293] In an aspect, a disclosed method can further comprise administering to the subject one or more additional anti-cancer therapies. In an aspect, a disclosed anti-cancer therapy can comprise endocrine therapy, radiotherapy, hormone therapy, gene therapy, thermal therapy, ultrasound therapy, or any combination thereof. In an aspect, a disclosed anti-cancer therapy can comprise one or more chemotherapeutic agents. In an aspect, a disclosed chemotherapeutic agent can comprise an anthracycline, a vinca alkaloid, an alkylating agent, an immune cell antibody, an antimetabolite, a TNFR glucocorticoid induced TNFR related protein (GITR) agonist, a proteasome inhibitor, an immunomodulator, or any combination thereof. In an aspect, a disclosed chemotherapeutic agent can comprise 5-fluorouracil (Adrucil, Efudex), 6-mercaptopurine (Purinethol), 6-thioguanine, aclarubicin or aclacinomycin A, alemtuzamab (Lemtrada), anastrozole (Arimidex), bicalutamide (Casodex), bleomycin sulfate (Blenoxane), bortezomib (Velcade), busulfan (Myleran), busulfan injection (Busulfex), capecitabine (Xeloda), carboplatin (Paraplatin), carmustine (BiCNU), chlorambucil (Leukeran), cisplatin (Platinol), cladribine (Leustatin), Cosmegan, cyclophosphamide (Cytoxan or Neosar), cyclophosphamide, cytarabinePolsinelli 24-3026-WO liposome injection (DepoCyt), cytarabine, cytosine arabinoside (Cytosar-U), dacarbazine (DTIC- Dome), dactinomycin (Cosmegen), daunorubicin citrate liposome injection (DaunoXome), daunorubicin hydrochloride (Cerubidine), dexamethasone, docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin, Rubex), etoposide (Vepesid), fludarabine phosphate (Fludara), flutamide (Eulexin), folic acid antagonists, gemcitabine (difluorodeoxycitidine), gemtuzumab, gliotoxin, hydroxyurea (Hydrea), Idarubicin (Idamycin), ifosfamide (IFEX), ifosfamide, irinotecan (Camptosar), L-asparaginase (ELSPAR), lenalidomide), leucovorin calcium, melphalan (Alkeran), melphalan, methotrexate (Folex), mitoxantrone (Novantrone), mylotarg, N4- pentoxycarbonyl-5 deoxy-5-fluorocytidine, nab-paclitaxel (Abraxane), paclitaxel (Taxol), pentostatin, phoenix (Yttrium90 / MX-DTPA), polifeprosan 20 with carmustine implant (Gliadel), purine analogs and adenosine deaminase inhibitors (fludarabine), pyrimidine analogs, rituximab, tamoxifen citrate (Nolvadex), temozolomide), teniposide (Vumon), tezacitibine, thalidomide or a thalidomide derivative, thiotepa, tirapazamine (Tirazone), topotecan hydrochloride for injection (Hycamptin), tositumomab), vinblastine (Velban), vinblastine, vincristine (Oncovin), vindesine, vinorelbine (Navelbine), or any combination thereof.

[0294] In an aspect, following the administering step, (i) the risk of developing metastases can be prevented and / or decreased; (ii) the survival of the subject can be prolonged; (iii) the subject’s quality of life can be enhanced and / or improved; (iv) the likelihood of surgical intervention can be reduced and / or minimized; (v) preventing and / or delaying recurrence of the cancer; (vi) the size of one or more tumors in the subject can be reduced and / or decreased; (vii) one or more tumors in the subject can be eliminated; (viii) extending and / or prolonging disease-free or tumor-free survival time; (ix) increasing and / or lengthening overall survival time; (x) reducing and / or minimizing the frequency of treatment; (xi) relieving and / or ameliorating one or more symptoms of the cancer; (xii) reducing and / or decreasing tumor burden, (ix) preventing and / or facilitating surgical intervention; (xiii) normal metabolism of one or more organ systems in the subject can be improved and / or restored, (xiv) one or more aspects of cellular homeostasis and / or cellular functionality, and / or metabolic dysregulation can be restored and / or improved, or (xv) any combination thereof.

[0295] In an aspect of a disclosed method, administering one or more disclosed anti-KRAS antibodies can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering one or more disclosed anti- KRAS antibodies can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering a disclosed compositionPolsinelli 24-3026-WO comprising one or more disclosed anti-KRAS antibodies can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses).

[0296] In an aspect, a therapeutically effective amount of a disclosed anti-KRAS antibody can comprise about 1 ng / kg body weight / day to about 100 ng / kg body weight / day, about 10 ng / kg body weight / day to about 1 μg / kg body, about 100 ng / kg body weight / day to about 10 μg / kg body, about 1 μg / kg body weight / day to about 100 μg / kg body, about 10 μg / kg body weight / day to about 1 mg / kg body, about 100 μg / kg body weight / day to about 10 mg / kg body, or about 1 mg / kg body weight / day to about 100 mg / kg body weight / day. In an aspect, a therapeutically effective amount of a disclosed anti-KRAS antibody can comprise about 10 mg / kg body weight / day, about 20 mg / kg body weight / day, about 30 mg / kg body weight / day, about 40 mg / kg body weight / day, about 50 mg / kg body weight / day, about 60 mg / kg body weight / day, about 70 mg / kg body weight / day, about 80 mg / kg body weight / day, about 90 mg / kg body weight / day, or about 100 mg / kg body weight / day.

[0297] In an aspect, a disclosed subject can present with one or more cancerous solid tumors, metastatic nodes, or any combination thereof. In any aspect, a subject herein can have a cancerous tumor cell source that can be less than about 0.2 cm3to at least about 20 cm3or greater, at least about 2 cm3to at least about 18 cm3or greater, at least about 3 cm3to at least about 15 cm3or greater, at least about 4 cm3to at least about 12 cm3or greater, at least about 5 cm3to at least about 10 cm3or greater, or at least about 6 cm3to at least about 8 cm3or greater.

[0298] In an aspect, a disclosed method of treating cancer and / or slowing disease progression can result in a reduction in size of a tumor. In an aspect, a reduction in size of a tumor may also be referred to as “tumor regression”. In an aspect, after treatment, tumor size can be reduced by at least 5% relative to its size prior to treatment. In an aspect, tumor size can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% relative to its size prior to treatment. Tumor size can be measured by any reproducible means of measurement. Tumor size can be measured as a diameter of the tumor.

[0299] In an aspect, a disclosed method of treating cancer and / or slowing disease progression can result in a reduction in tumor volume. In an aspect, after treatment, tumor volume can be reduced by at least 5% relative to the volume prior to treatment. In an aspect, tumor volume can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% relative to its volume prior to treatment. Tumor volume can be measured by any reproducible means of measurement.

[0300] In an aspect, a disclosed method of treating cancer and / or slowing disease progression can result in a decrease in number of tumors. In an aspect, after treatment, tumor number can bePolsinelli 24-3026-WO reduced by at least 5% relative to number prior to treatment. In an aspect, tumor number can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% relative to its volume prior to treatment. Number of tumors can be measured by any reproducible means of measurement. The number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2×, 3×, 4×, 5×, 10×, or 50×).

[0301] In an aspect, a disclosed method of treating cancer and / or slowing disease progression can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. In an aspect, after treatment, the number of metastatic lesions can be reduced by at least 5% relative to number prior to treatment. In an aspect, the number of metastatic lesions can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% relative to number prior to treatment. The number of metastatic lesions can be measured by any reproducible means of measurement. The number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specified magnification (e.g., 2×, 3×, 4×, 5×, 10×, or 50×).

[0302] In an aspect, a disclosed method of treating cancer and / or slowing disease progression can result in an increase in survival time of a treated subject when, for example, compared to a subject not receiving treatment. In an aspect, survival team can be increased at least 30 days, at least 60 days, at least 90 days, or at least 120 days. In an aspect, an increase in survival time of a population can be measured by any reproducible means. In an aspect, an increase in survival time of a population can be measured, for example, by calculating for a population the average length of survival following initiation of treatment with a disclosed composition.

[0303] In an aspect, a disclosed subject has already received or is actively receiving one or more disclosed targeted therapies. In an aspect, a subject is treatment-naïve.

[0304] In an aspect of a disclosed method of treating and / or preventing cancer, administering a disclosed treatment regimen can comprise intravenous administration. In an aspect, a disclosed treatment regimen can be administered to a subject intravenously using, for example, a dual- channel infusion pump or two single channel pumps and central venous catheter. In an aspect, a disclosed IV administration of a disclosed treatment regimen can occur once every four hours at the infusion rate of from about 50 mL / hr to about 250 mL / hr (e.g., about 50, 75, 100, 125, 150, 175, 200, 225, 250 mL / hr) depending on the subject’s age and condition / tolerance. In an aspect, one or more anti-KRAS antibodies or a pharmaceutical formulation thereof can be delivered via an ambulatory infusion pump and subclavian catheter.Polsinelli 24-3026-WO

[0305] In an aspect, local administration can comprise delivery to one or more of the subject’s body systems having cancerous cells or tumorous growth. In an aspect, the subject’s one or more body systems having cancerous cells or tumorous growth can comprise the subject’s cardiovascular system, the subject’s digestive system, the subject’s endocrine system, the subject lymphatic system, the subject’s muscular system, the subject’s nervous system, the subject’s reproductive system, the subject’s respiratory system, the subject’s skeletal system, the subject’s urinary system, the subject’s integumentary system, or any combination thereof.

[0306] In an aspect, a disclosed method of treating and / or preventing cancer can comprise titrating the dose of a disclosed treatment regimen. In an aspect, a disclosed method of treating and / or preventing cancer can comprise titrating the dose of one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof. In an aspect, a disclosed method of treating and / or preventing cancer can comprise titrating the dose of one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof, a disclosed targeted therapy, a disclosed composition, a disclosed pharmaceutical formulation, a disclosed therapeutic agent, a disclosed immune modulator, a disclosed proteasome inhibitor, a disclosed small molecule, a disclosed endonuclease, a disclosed oligonucleotide, a disclosed RNA therapeutic, or any combination thereof to identify an effective dose and / or to identify an effective dose eliciting only mild adverse and / or side effects.

[0307] In an aspect, a disclosed method of treating and / or preventing cancer can comprise titrating the dose of a disclosed treatment regimen in a specific or disclosed subject. In an aspect, a disclosed method of treating and / or preventing cancer can comprise titrating the dose of one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof in a specific or disclosed subject. In an aspect, a disclosed method of treating and / or preventing cancer can comprise titrating the dose of a disclosed composition, a disclosed pharmaceutical formulation, a disclosed therapeutic agent, a disclosed immune modulator, a disclosed proteasome inhibitor, a disclosed small molecule, a disclosed endonuclease, a disclosed oligonucleotide, a disclosed RNA therapeutic, or any combination thereof to identify an effective dose and / or to identify an effective dose eliciting only mild adverse and / or side effects for a specific or disclosed subject.

[0308] In an aspect, administering comprises administering to the subject the maximum tolerated dose of the one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof. In an aspect, administering comprises administering to the subject less than the maximum tolerated dose of the one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof.

[0309] In an aspect, IV administration of a disclosed treatment regimen can comprise an outpatient setting. In an aspect, one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof can be administered prior to, concurrent with, or after administering of a disclosed targetedPolsinelli 24-3026-WO therapy. In an aspect, the order of administering the one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof and the administering of any other therapeutic agent and / or targeted therapy can change during a treatment regimen.

[0310] In an aspect, a disclosed method of treating and / or preventing cancer can further comprise obtaining a biological sample from the subject prior to administering a disclosed treatment regimen. In an aspect, a disclosed method of treating and / or preventing cancer can further comprise obtaining a biological sample from the subject after administering a disclosed treatment regimen. In an aspect, a disclosed method of treating and / or preventing cancer can further comprise subjecting the biological sample to a cell-free DNA (cfDNA) analysis. cfDNA analyses are known to the skilled person in the art. In an aspect, a disclosed cfDNA analysis can be repeated one or more times. In an aspect, a disclosed obtaining step can be repeated one or more times.

[0311] In an aspect of a disclosed method of treating and / or preventing cancer, a disclosed cfDNA analysis can comprise next generation sequencing. In an aspect, next generation sequencing (NGS) can comprise using one or more commercially available platforms. Commercially available NGS sequencing platforms can comprise, for example, Guardant360 CDx (Guardant Health, Inc.), FoundationOne CDx (F1CDx) (Foundation Medicine, Inc.), or Tempus xT (Tempus). In an aspect, a disclosed method can identify and / or characterize a disclosed mutant KRAS.

[0312] In an aspect of a disclosed method of treating and / or preventing cancer, next generation sequencing can comprise sequencing one or more cancer related genes. In an aspect of a disclosed method of treating and / or preventing cancer, sequencing one or more cancer related genes can comprise identifying one or more genomic aberrations. In an aspect, one or more genomic aberrations can comprise somatic genomic aberrations. In an aspect, the disclosed one or more somatic genomic aberrations can comprise mutations, insertions, deletions, chromosomal rearrangements, copy number aberrations, or any combination thereof.

[0313] In an aspect of a disclosed method, one or more genomic aberrations in the biological sample can be detected. In an aspect, a disclosed method can further comprise detecting one or more genomic aberrations in the biological sample. In an aspect, a disclosed method can further comprise identifying one or more genomic aberrations in a panel of genes. In an aspect, disclosed genomic aberrations can be identified in a panel of genes. In an aspect, a disclosed panel of genes can comprise at least one gene, at least two genes, 3 or more genes, 5 or more genes, 7 or more genes, or 10 or more genes. In an aspect, a disclosed panel of genes can comprise 2 or more genes, 3 or more genes, 4 or more genes, 5 or more genes, 6 or more genes, 7 or more genes, 8 or morePolsinelli 24-3026-WO genes, 9 or more genes, or 10 or more genes. In an aspect, a disclosed panel of genes can comprise any combination of disclosed genes or disclosed cancer-related genes.

[0314] In an aspect, a disclosed method can comprise detecting the expression of one or more disclosed genes and / or one or more disclosed gene aberrations.

[0315] In an aspect of a disclosed method, the level of expression of one or more genomic aberrations can be tied to the aggressiveness and / or likelihood of survival. In an aspect of a disclosed method, the expression of the one or more genomic aberrations in a biological sample can be associated with the pathophysiological status of the subject suffering from breast cancer. In an aspect of a disclosed method, the absence and / or the presence of one or more genomic aberrations can be tied to the aggressiveness and / or likelihood of survival. In an aspect of a disclosed method, the absence and / or the presence of one or more genomic aberrations in a biological sample can be associated with the pathophysiological status of the subject suffering from breast cancer. In an aspect, a disclosed method can further comprise generating a library and / or database comprising a listing of genes and / or genomic aberrations affected by the administration of one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof only. In an aspect, a disclosed method can further comprise generating a library and / or database comprising a listing of genes and / or genomic aberrations affected by the administration of one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof and one or more targeted therapies.

[0316] In an aspect of a disclosed method of treating and / or preventing cancer, a disclosed cfDNA analysis can comprises quantification of one or more cancer related genes. In an aspect, if the expression and / or amount and / or presence of the disclosed one or more genomic aberrations in the pre-treatment biological sample is higher than the expression and / or amount and / or presence of the same one or more genomic aberrations in a control sample, then a disclosed method of treating and / or preventing cancer can comprise diagnosing the subject as being in need of precision cancer treatment. In an aspect, a disclosed control sample can be a sample obtained from a subject not having cancer. In an aspect, a disclosed control sample can be a pooled sample obtained from more than one subject not having cancer.

[0317] In an aspect, a disclosed method can comprise generating a control sample and / or a pooled control sample. In an aspect, a disclosed method can comprise generating a reference sample and / or a pooled reference sample. In an aspect, a disclosed method can comprise generating a range of control samples and / or pooled control samples. In an aspect, a disclosed method can comprise generating a range of reference samples and / or pooled reference samples.Polsinelli 24-3026-WO

[0318] In an aspect, if the expression and / or amount and / or presence of the disclosed one or more genomic aberrations in the post-treatment biological sample is lower than the expression and / or amount and / or presence of the same one or more genomic aberrations in a pre-treatment sample, then a disclosed method of treating and / or preventing cancer can comprise continuing to administer to the subject a disclosed treatment regimen. In an aspect, if the expression and / or amount and / or presence of the disclosed one or more genomic aberrations in the post-treatment biological sample is lower than the expression and / or amount and / or presence of the same one or more genomic aberrations in a prior post-treatment sample, then a disclosed method of treating and / or preventing cancer of treating and / or preventing cancer can comprise continuing to administer to the subject a disclosed treatment regimen.

[0319] In an aspect, a disclosed method of treating and / or preventing cancer can further comprise measuring the subject’s tumor response to the precision cancer treatment. In an aspect, a subject’s tumor response can comprise a partial response or a complete response. In an aspect, a disclosed partial response can comprise a decrease in the size of a tumor or a decrease in one or more tumors by 25% or more when compared to the size of the same tumor or the same one or more tumors prior to treatment. In an aspect, a disclosed partial response can comprise a decrease in the size of a tumor or a decrease in one or more tumors by 50% or more when compared to the size of the same tumor or the same one or more tumors prior to treatment. In an aspect, a disclosed partial response can comprise a decrease in the size of a tumor or a decrease in one more tumors by about 100% or more when compared to the size of the same tumor or the same one or more tumors prior to treatment.

[0320] In an aspect, a complete response can be defined as complete disappearance of all tumors with no recurrence of tumors for at least four weeks. In an aspect, a partial response can be defined as a 50% reduction in total tumor size with such reduction lasting at least four weeks. In an aspect, stable disease can be defined as less than 50% reduction in size but no more than 25% increase in size of the tumor mass lasting for at least twelve weeks.

[0321] In an aspect, a disclosed method of treating and / or preventing cancer can further comprise measuring the subject’s molecular response to a disclosed treatment regimen. In an aspect, a disclosed molecular response can comprise a decrease in the number of somatic genomic aberrations in a disclosed biological sample obtained from the subject. In an aspect, disclosed somatic genomic aberrations can comprise mutations, insertions, deletions, chromosomal rearrangements, copy number aberrations, fusions, or any combination thereof.

[0322] In an aspect, a disclosed method of treating cancer and / or slowing disease progression can further comprise collecting one or more blood and / or biological samples from a subject at the samePolsinelli 24-3026-WO time or at different times. For example, in an aspect, a blood sample and / or a biological sample can be collected from a subject at a pre-determined interval. In an aspect, a pre-determined interval can be once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, or at a longer interval. In an aspect, a pre-determined interval can be once a month, once every 2 months, once every 3 months, once every 5 months, once every 5 months, once every 6 months, or at a longer interval. In an aspect, a blood sample and / or a biological sample can be collected from a subject prior to treatment, during treatment, after treatment, or any combination thereof. In an aspect, a disclosed blood and / or a disclosed biological sample can be collected from a subject at any time deemed medically and / or clinically appropriate by the skilled clinician.

[0323] In an aspect, a disclosed molecular marker that can determine one or more suitable precision cancer treatments in one or more disclosed methods can be measured from a sample by high-density expression array, DNA microarray, polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), real-time quantitative reverse transcription PCR (qRT-PCR), serial analysis of gene expression (SAGE), spotted cDNA arrays, GeneChip, spotted oligo arrays, bead arrays, RNA Seq, tiling array, northern blotting, hybridization microarray, in situ hybridization, whole-exome sequencing, whole-genome sequencing, liquid biopsy, next-generation sequencing, or any combination thereof.

[0324] In an aspect, a disclosed molecular marker can determine one or more suitable precision cancer treatments for use in a disclosed method of treating and / or preventing cancer can determined from the nucleic acid sequence of at least one of circulating DNA and / or RNA. In an aspect, a disclosed molecular marker can be assessed from circulating tumor DNA and / or RNA (ctDNA and / or ctRNA); circulating cell-free DNA and / or RNA (cfDNA, cfRNA); or any combination thereof. ctDNA / ctRNA refers to tumor-derived fragmented DNA in the bloodstream that is not associated with cells. cfDNA / cfRNA refers to DNA that is freely circulating in the bloodstream, but is not necessarily of tumor origin. In an aspect, cfDNA / ctDNA can include any whole or fragmented genomic DNA, or mitochondrial DNA, and / or cfRNA / ctRNA can include mRNA, tRNA, microRNA, small interfering RNA, long non-coding RNA (1 ncRNA). In an aspect, cfDNA and / or ctDNA can be a fragmented DNA with a length of at least about 50 base pair (bp), about 100 bp, about 200 bp, about 500 bp, or about 1 kbp. In an aspect, cfRNA and / or ctRNA can be a full length or a fragment of mRNA (e.g., at least 70% of full-length, at least 50% of full length, at least 30% of full length, etc.). In an aspect, a disclosed molecular marker can be directed against any cancer-related gene disclosed herein.Polsinelli 24-3026-WO

[0325] In an aspect, a disclosed method can further comprise surgically resecting the tumor from the subject. In an aspect, a disclosed method can further comprise subjecting the subject to one or more invasive or non-invasive diagnostic assessments. In an aspect, a disclosed non-invasive diagnostic assessment can comprise x-rays, computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasounds, positron emission tomography (PET) scans, or any combination. In an aspect, a disclosed invasive diagnostic assessment can comprise a tissue biopsy.

[0326] For example, in an aspect, repeating one or more disclosed steps of a disclosed method can comprise repeating the administering to the subject the treatment regimen, one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof, the targeted therapy, or any combination thereof, repeating the measuring of the subject’s tumor response, repeating the obtaining of a biological sample from the subject, repeating the subjecting the biological sample to cfDNA analysis, repeating the administering of one or more additional therapeutic agents, or any combination thereof.

[0327] In an aspect, a disclosed molecular marker can be detected, quantified, and / or analyzed over time (at different time points) to determine the effectiveness of a disclosed treatment regimen (e.g., one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof) to the subject and / or to determine the response of a subject or subject’s tumor to the precision cancer treatment (e.g., developing resistance, susceptibility, etc.). In an aspect, a disclosed method can comprise obtaining multiple measurements over time from the same subject and same sample may be quantified at a single time point or over time. In an aspect, a disclosed treatment regimen treatment (e.g., a disclosed treatment regimen comprising one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof) can be designed and / or determined based on the cancer status and / or the changes / types of one or more molecular markers. In an aspect, the likelihood of success of a disclosed treatment regimen can be determined based on the cancer status and the type / quantity of one or more molecular markers.

[0328] In an aspect, a disclosed molecular marker can be derived from a gene expressed in one or more cells of a tumor or in an immune cell and can indicate immune suppressive tumor microenvironment, the development of cancer sternness, the onset of metastasis, cancer status, or any combination thereof. In an aspect, a disclosed molecular marker can be the protein or peptide encoded by the gene from which the molecular marker is derived and can be targeted by an antagonist or any other type of binding molecule to inhibit the function of the peptide.

[0329] Thus, in an aspect, increased expression (e.g., above a predetermined threshold) of a disclosed molecular marker derived from a disclosed gene related to immune suppressive tumorPolsinelli 24-3026-WO microenvironment can implicate the presence of immune suppressive tumor microenvironment, and can also implicate that an antagonist to the peptide encoded by the gene related to immune suppressive tumor microenvironment can have a high likelihood of success to inhibit the progress of the cancer by inhibiting immune suppressive tumor microenvironment and further promoting immune cell activity against tumor cells in such microenvironment. In an aspect, once the molecular marker has been identified, any suitable antagonist to a target gene or protein product can be used. For example, in an aspect, a specific kinase can be targeted by a kinase inhibitor, or a specific signaling receptor can be targeted by synthetic ligand, or a specific checkpoint receptor targeted by synthetic antagonist or antibody, etc. In an aspect, a disclosed antagonists to a target molecule herein can be administered before, after, or in combination with one or more disclosed anti-KRAS antibodies or a pharmaceutical formulation thereof.

[0330] In an aspect, a subject can be a human patient. In an aspect a subject can be any age (e.g., geriatric, adult, young adult, teenager, tween, adolescent, child, toddler, baby, or infant), can be male or female, can be any nationality, can be of any ethnicity, and / or can be of any race. In an aspect, a subject can have terminal cancer. In an aspect, a disclosed subject can have any cancer characterized by and / or driving by a mutant KRAS. In an aspect, a disclosed subject can have a combination of cancers including one or more characterized by and / or driving by a mutant KRAS.

[0331] In an aspect, a disclosed targeted therapy can comprise one or more monoclonal antibodies.

[0332] In an aspect, a disclosed monoclonal antibody can comprise an angiogenesis inhibitor (e.g., bevacizumab), a HER-2 targeted agent (e.g., trastuzumab, pertuzumab, etc.), an anti-CD20 monoclonal antibody (e.g., rituximab, obinutuzumab, etc.), or any combination thereof. In an aspect, a disclosed targeted therapy can comprise one or more small molecule inhibitors. In an aspect, a disclosed small molecule inhibitor can comprise a tyrosine kinase inhibitor (e.g., erlotinib, sunitinib, imatinib, dasatinib, etc.), a mTOR inhibitor (e.g., everolimus), a PARP inhibitor (e.g., olaparib), a CDK inhibitor (e.g., palbociclib, ribociclib, abermaciclib, etc.), a CD4 and / or CD6 inhibitor, or any combination thereof.

[0333] In an aspect, a disclosed targeted therapy can comprise abagovomab, abciximab, abituzumab, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afelimomab, afutuzumab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, arcitumomab, ascrinvacumab, aselizumab, atezolizumab, atinumab, atlizumab (tocilizumab), atorolimumab, bapineuzumab, basiliximab, bavituximab, bectumomab, begelomab, belimumab, benralizumab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, bivatuzumab mertansine, blinatumomab, blosozumab, bococizumab, brentuximPolsinelli 24-3026-WO abvedotin, briakinumab, brodalumab, brolucizumab, brontictuzumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide, carlumab, catumaxomab, cbr96-doxorubicin immunoconjugate, cedelizumab, certolizumab pegol, cetuximab, citatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, coltuximab ravtansine, conatumumab, concizumab, crenezumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrekumab, demcizumab, denintuzumab mafodotin, denosumab, derlotuximab biotin, detumomab, dinutuximab, diridavumab, dorlimomab aritox, drozitumab, duligotumab, dupilumab, durvalumab, dusigitumab, ecromeximab, eculizumab, edobacomab, edrecolomab, efalizumab, efungumab, eldelumab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emibetuzumab, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblituzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, erlizumab, ertumaxomab, etanercept, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, farletuzumab, fasinumab, felvizumab, fezakinumab, ficlatuzumab, figitumumab, firivumab, flanvotumab, fletikumab, fontolizumab, foralumab, foravirumab, fresolimumab, fulranumab, futuximab, galiximab, ganitumab, gantenerumab, gavilimomab, gemtuzumab ozogamicin, gevokizumab, girentuximab, glembatumumab vedotin, golimumab, gomiliximab, guselkumab, ibalizumab, ibritumomab tiuxetan, icrucumab, idarucizumab, igovomab, imalumab, imciromab, imgatuzumab, inclacumab, indatuximab ravtansine, indusatumab vedotin, infliximab, inolimomab, inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, isatuximab, itolizumab, ixekizumab, keliximab, labetuzumab, lambrolizumab, lampalizumab, lebrikizumab, lemalesomab, lenzilumab, lerdelimumab, lexatumumab, libivirumab, lifastuzumab vedotin, ligelizumab, lilotomab satetraxetan, lintuzumab, lirilumab, lodelcizumab, lokivetmab, lorvotuzumab mertansine, lucatumumab, lulizumab pegol, lumiliximab, lumretuzumab, mapatumumab, margetuximab, maslimomab, matuzumab, mavrilimumab, mepolizumab, metelimumab, milatuzumab, minretumomab, mirvetuximab soravtansine, mitumomab, mogamulizumab, morolimumab, motavizumab, moxetumomab pasudotox, muromonab-cd3, nacolomab tafenatox, namilumab, naptumomab estafenatox, narnatumab, natalizumab, nebacumab, necitumumab, nemolizumab, nerelimomab, nesvacumab, nimotuzumab, nivolumab, nofetumomab merpentan, obiltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab monatox, oregovomab, orticumab, otelixizumab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, panitumumab, pankomab, panobacumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, pembrolizumab, pemtumomab, perakizumab,Polsinelli 24-3026-WO pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placulumab, polatuzumab vedotin, ponezumab, priliximab, pritoxaximab, pritumumab, quilizumab, racotumomab, radretumab, rafivirumab, ralpancizumab, ramucirumab, ranibizumab, raxibacumab, refanezumab, regavirumab, reslizumab, rilotumumab, rinucumab, rituximab, robatumumab, roledumab, romosozumab, rontalizumab, rovelizumab, ruplizumab, sacituzumab govitecan, samalizumab, sarilumab, satumomab pendetide, secukinumab, seribantumab, setoxaximab, sevirumab, sibrotuzumab, sifalimumab, siltuximab, simtuzumab, siplizumab, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tanezumab, taplitumomab paptox, tarextumab, tefibazumab, telimomab aritox, tenatumomab, teneliximab, teplizumab, teprotumumab, tesidolumab, tetulomab, ticilimumab, tigatuzumab, tildrakizumab, tocilizumab, toralizumab, tosatoxumab, tositumomab, tovetumab, tralokinumab, trastuzumab, tregalizumab, tremelimumab, trevogrumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, ulocuplumab, urelumab, urtoxazumab, ustekinumab, vandortuzumab vedotin, vantictumab, vanucizumab, vapaliximab, varlilumab, vatelizumab, vedolizumab, veltuzumab, vepalimomab, vesencumab, visilizumab, volociximab, vorsetuzumab mafodotin, votumumab, zalutumumab, zanolimumab, zatuximab, ziralimumab, zolimomab aritox, or any combination thereof.

[0334] In an aspect, a disclosed targeted therapy can comprise abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, alemtuzumab, alpelisib, atezolizumab, avelumab, axitinib, bevacizumab, binimetinib, blinatumomab, bosutinib, brentuximab, brigatinib, cabozantinib, carfilzomib, cemiplimab, ceritinib, cetuximab, gilteritinib, cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, daratumumab, dasatinib, denosumab, dinutuximab, durvalumab, duvelisib, elotuzumab, encorafenib, entrectinib, erdafitinib, erlotinib, fam-trastuzumab deruxtecan-nxki, gefitinib, gemtuzumab, ibritumomab tiuxetan, ibrutinib, imatinib, inotuzumab, ipilumumab, ivosidenib, lapatinib, larotrectinib, Lenvatinib, lorlatinib, margetuximab-cmkb, necitumumab, neratinib, nilotinib, niraparib, nivolumab, obinutuzumab, ofatumumab, olaparib, olaratumab, osimertinib, palbociclib, panitumumab, pazopanib, pembrolizumab, pertuzumab, ponatinib, ramucirumab, regorafenib, ribociclib, rituximab, rucaparib, sorafenib, sunitinib, talazoparib, tivozanib, tositumomab, trametinib, trastuzumab, tucatinib, vandetanib, vemurafenib, vismodegib, or any combination thereof.

[0335] In an aspect, a disclosed targeted therapy for oral administration can comprise abemaciclib, afatinib, alectinib, alpelisib, axitinib, binimetinib, bosutinib, brigatinib, cabozantinib, cobimetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelisib, encorafenib, entrectinib, erdafitinib,Polsinelli 24-3026-WO erlotinib, gefitinib, gilteritinib, ibrutinib, imatinib mesylate, ivosidenib, lapatinib, larotrectinib, lorlatinib, lenvatinb, neratinib, nilotinib, niraparib, olaparib, osimertinib palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, rucaparib, sorafenib, sunitinib malate, talazoparib, tivozanib, trametinib, vandetanib, vemurafenib, vismodegib, or any combination thereof.

[0336] In an aspect, a disclosed targeted therapy for intravenous administration can comprise ado- trastuzumab emtansine, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab vedotin, carfilzomib, cetuximab, cemiplimab-rwlc, certinib, copanlisib, daratumumab, dinutuximab, durvalumab, elotuzumab, fam-trastuzumab deruxtecan-nxki, gemtuzumab ozogamicin, ibritumomab tiuxetan, inotuzumab ozogamicin, ipilimumab, margetuximab-cmkb, necitumumab, nivolumab, obinutuzumab, olaratumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab and iodine I131 tositumomab, trastuzumab, ublituximab-xiiy, or any combination thereof.

[0337] In an aspect, a disclosed targeted therapy for subcutaneous administration can comprise denosumab, ofatumumab, or any combination thereof.

[0338] In an aspect, a disclosed method of treating and / or preventing cancer can comprise administering to the subject a therapeutically effective amount of a targeted immunotherapy agent (e.g., fam-trastuzumab-deruxtecan-nxki; trastuzumab; Herceptin Hylecta (injectable Herceptin); Herceptin biosimilars (e.g., Herzuma, Kanjinti, Ogivri, Ontruzant, and Trazimera); ado- trastuzumab emtansine; margetuximab-cmkb; pertuzumab, trastuzumab, and hyaluronidase-zzxf; pertuzumab; sacituzumab govitecan-hziy; or any combination thereof).

[0339] In an aspect, a disclosed method can be modified or one or more steps of a disclosed method can be modified. In an aspect, a disclosed method of treating and / or preventing cancer and / or metastatic cancer can comprise modifying or changing one or more features or aspects of one or more steps. In an aspect, a method can be altered by changing the amount of a disclosed treatment regimen, a disclosed anti-KRAS antibody, a disclosed targeted therapy, a disclosed pharmaceutical formulation, a disclosed anti-chemokine, a disclosed anti-cancer agent, a disclosed chemotherapeutic agent, or a combination thereof administered to a subject, or by changing the frequency of administration of disclosed treatment regimen, a disclosed anti-KRAS antibody, a disclosed targeted therapy, a disclosed pharmaceutical formulation, a disclosed anti-chemokine, a disclosed anti-cancer agent, a disclosed chemotherapeutic agents, or a combination thereof to a subject, by changing the duration of time that disclosed treatment regimen, a disclosed anti-KRAS antibody, a disclosed targeted therapy, a disclosed pharmaceutical formulation, a disclosed anti- chemokine, a disclosed anti-cancer agent, a disclosed chemotherapeutic agent, or a combination thereof is administered to a subject, or by substituting for one or more of the disclosed componentsPolsinelli 24-3026-WO and / or reagents with a similar or equivalent component and / or reagent. The same applies to all disclosed treatment regimens, disclosed anti-KRAS antibodies, disclosed targeted therapies, disclosed pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed chemotherapeutic agents, or combinations thereof.

[0340] In an aspect, a disclosed method can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, the subject’s life expectancy can be compared to the life expectancy of a control (i.e., no treatment with a disclosed anti-KRAS antibody). In an aspect, a control can be a subject not receiving a disclosed pharmaceutical composition. In an aspect, a control can be a pooled number of subjects not receiving a disclosed pharmaceutical composition. In an aspect, a control is one or more subjects having the same type of cancer condition as the subject. In an aspect, life expectancy can be defined as the time at which 50 percent of subjects are alive and 50 percent have passed away.

[0341] In an aspect, patient life expectancy can be indefinite following treatment with a disclosed method. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subject with the identical or near identical viral infection and the identical or near identical predicted outcome. In an aspect, patient life expectancy can be indefinite following treatment with a disclosed method. In an aspect, patient life expectancy can be increased at least about 5% to at least about 100%, at least about 10% to at least about 95%, at least about 20% to at least about 80%, at least about 40% to at least about 60% compared to an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, life expectancy can be increased at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100% compared to an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, life expectancy can be increased at least about 5% to at least about 10%, at least about 10% to at least about 15%, at least about 15% to at least about 20%, at least about 20% to at least about 25%, at least about 25% to at least about 30%, at least about 30% to at least about 35%, at least about 35% to at least about 40%, at least about 40% to at least about 45%, at least about 45% to at least about 50%, at least about 50% to at least about 55%, at least about 55%Polsinelli 24-3026-WO to at least about 60%, at least about 60% to at least about 65%, at least about 65% to at least about 70%, at least about 70% to at least about 75%, at least about 75% to at least about 80%, at least about 80% to at least about 85%, at least about 85% to at least about 90%, at least about 90% to at least about 95%, at least about 95% to at least about 100% compared to an untreated patient with the identical or near identical disease condition and the identical or near identical predicted outcome.

[0342] In an aspect, a disclosed method can further comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, a disclosed method can further comprise continuing to treat the subject. In an aspect, continuing to treat the subject can comprise continuing to administer a disclosed composition (i.e., one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof).

[0343] In an aspect, in the presence of adverse effects, a disclosed method can further comprise modifying one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method can comprise modifying one or more administering steps. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount of a disclosed composition (i.e., one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof) administered to the subject, changing the frequency of a disclosed composition (i.e., one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof) administration, changing the duration of a disclosed composition (i.e., one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof) administration, changing the route of a disclosed composition (i.e., one or more disclosed anti- KRAS antibodies and / or a pharmaceutical formulation thereof) administration, or any combination thereof. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount a disclosed composition (i.e., one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof) administered to the subject, changing the frequency of a disclosed composition (i.e., one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof) administration, changing the duration of a disclosed composition (i.e., one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof) administration, changing the route of a disclosed composition (i.e., one or more disclosed anti- KRAS antibodies and / or a pharmaceutical formulation thereof), or any combination thereof.

[0344] In an aspect, a disclosed method can reduce the risk of developing one or more metastases. A reduction in the risk of developing one or more metastases comprises a reduction of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount in the risk of metastases whenPolsinelli 24-3026-WO compared to a control subject (such as, for example, a subject that has not received one or more disclosed anti-KRAS antibodies and / or a pharmaceutical formulation thereof).

[0345] In an aspect, a disclosed method can comprise improving and / or enhancing the subject’s quality of life and / or movement...

Claims

Polsinelli 24-3026-WO IX. CLAIMS What is claimed is:

1. An anti-KRAS antibody, comprising: an IgG backbone and a polymeric immunoglobulin receptor (PIGR)-binding peptide having the sequence set forth in SEQ ID NO:41 or SEQ ID NO:

143.

2. The anti-KRAS antibody of Claim 1, wherein the antibody comprises: a variable light chain region (VL) comprising 3 complementarity determining regions (CDRs), and a variable heavy chain region (VH) comprising 3 CDRs, wherein the VH is linked to the PIGR-binding peptide.

3. The anti-KRAS antibody of Claim 2, wherein CDR1 in the VL comprises the sequence set forth in SEQ ID NO:64, wherein CDR2 comprises the sequence set forth in SEQ ID NO:65, and wherein CDR3 comprises the sequence set forth in SEQ ID NO:

66.

4. The anti-KRAS antibody of Claim 2 or Claim 3, wherein CDR1 in the VH comprises the sequence set forth in SEQ ID NO:58, wherein CDR2 comprises the sequence set forth in SEQ ID NO:59, and wherein CDR3 comprises the sequence set forth in SEQ ID NO:

60.

5. The anti-KRAS antibody of Claim 2, wherein CDR1 in the VL comprises the sequence set forth in SEQ ID NO:64, CDR2 comprises the sequence set forth in SEQ ID NO:65, and CDR3 comprises the sequence set forth in SEQ ID NO:66; and wherein CDR1 in the VH comprises the sequence set forth in SEQ ID NO:58, CDR2 comprises the sequence set forth in SEQ ID NO:59, and CDR3 comprises the sequence set forth in SEQ ID NO:

60.

6. The anti-KRAS antibody of Claim 2, wherein the VL comprises the sequence set forth in SEQ ID NO:18, and wherein the VH comprises the sequence set forth in SEQ ID NO:

01.

7. An anti-KRAS antibody, comprising: a variable light chain region (VL) comprising 3 complementarity determining regions (CDRs), and a variable heavy chain region (VH) comprising 3 CDRs and linked to a PIGR-binding peptide.

8. The anti-KRAS antibody of Claim 7, wherein the VL comprises the sequence set forth in SEQ ID NO:18, and wherein the VH comprises the sequence set forth in SEQ ID NO:07.Polsinelli 24-3026-WO 9. The anti-KRAS antibody of any preceding claim, wherein the IgG backbone comprises an IgG1 backbone, an IgG2 backbone, an IgG3 backbone, or an IgG4 backbone.

10. The anti-KRAS antibody of any preceding claim, wherein the binding of the PIGR-binding peptide to PIGR on a cell surface triggers transcytosis of the antibody into the cell; and wherein the antibody binds intracellular mutant KRAS and promotes the expulsion of the mutant KRAS from the cytoplasm of the cell.

11. The anti-KRAS antibody of Claim 10, wherein the mutant KRAS comprises KRASG12A, KRASG12C, KRASG12D, KRASG12R, KRASG12S, KRASG12V, KRASG12X, KRASG13C, KRASG13D, KRASG13X, KRASQ61H, KRASQ61L, KRASQ61K, KRASQ61R, KRASQ61X, KRASA146T, KRASA146V, KRASA146X, or any combination thereof.

12. The anti-KRAS antibody of any preceding claim, wherein the antibody slows or prevents tumor growth.

13. A nucleic acid molecule, comprising: a nucleic acid sequence encoding the anti-KRAS antibody of Claim 7.

14. The nucleic acid molecule of Claim 13, wherein the sequence encoding the VL comprises the sequence set forth in SEQ ID NO:

20.

15. The nucleic acid molecule of Claim 13, wherein the sequence encoding the VH comprises the sequence set forth in SEQ ID NO:

10.

16. A pharmaceutical formulation comprising the anti-KRAS antibody of any one of Claims 1 - 12 and one or more pharmaceutically acceptable carriers.

17. A method of treating a subject having cancer, the method comprising: administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical formulation of Claim 16.

18. The method of Claim 17, wherein the cancer is pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, bladder adenocarcinoma, endometroid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, non-small cell lung cancer, lung adenocarcinoma, squamous lung cancer, colorectal adenocarcinoma, or pancreatic carcinoma.

19. The method of Claim 17 or Claim 18, further comprising administering to the subject a therapeutically effective amount of one or more anti-cancer agents and / or anti-cancer therapies.

20. The method of any one of Claims 17-19, wherein following the administering step, (i) the risk of developing metastases is prevented and / or decreased, (ii) the survival of the subject is prolonged, (iii) the subject’s quality of life is enhanced and / or improved, (iv) the likelihoodPolsinelli 24-3026-WO of surgical intervention is reduced and / or minimized, (v) the size of one or more tumors in the subject is reduced and / or decreased, (vi) one or more tumors in the subject are eliminated, (vii) normal metabolism of one or more organ systems in the subject are improved and / or restored, (viii) one or more aspects of cellular homeostasis and / or cellular functionality, and / or metabolic dysregulation are restored and / or improved, or (ix) any combination thereof.

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