Multispecific EGFR antibodies and use in the treatment of cancer

Abstract

Provided herein are methods of treating an EGFR-positive (EGFR+) cancer in a subject in need thereof comprising administering a bispecific gamma delta (γδ)-T cell engager (BS-GDTE) comprising a first antigen-binding domain that specifically binds to EGFR and a second antigen-binding domain that binds to human Vδ2.

Description

MULTISPECIFIC EGFR ANTIBODIES AND USE IN THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application 63 / 609,103, filed December 12, 2023, the contents of which are incorporated herein by reference in its entirety.SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (SEAG_002_01WO_SeqList_ST26.xml; Size: 10,688 bytes; and Date of Creation: December 4, 2024) are herein incorporated by reference in its entirety.BACKGROUND

[0003] EGFR is a 170 kDa glycoprotein that consists of an extracellular receptor domain, a transmembrane region, and an intracellular domain with tyrosine kinase function. It is a receptor for members of the epidermal growth factor family of extracellular protein ligands such as epidermal growth factor (EGF), transforming growth factor alpha (TGF-a) or heparin- binding EGF-like growth factor. Under physiological conditions, the receptor is widely expressed in a number of tissues such as in the thyroid gland, skin, lung, colon, liver, kidney, or placenta tissues.

[0004] The EGFR and its downstream signaling pathways play key roles in oncogenesis: overexpression because of gene amplification and mutations affecting EGFR expression and / or activity can contribute to cancer due to over-activation or constitutive activation of downstream signaling pathways that lead to uncontrolled cell proliferation and evasion of apoptosis. EGFR targeting therapies have been developed, including receptor blocking monoclonal antibodies (mAb), e.g., cetuximab, panitumumab, necitumumab, and tyrosine kinase inhibitors, e.g., erlotinib, gefitinib.SUMMARY

[0005] The use of these previously described therapies is limited on the one hand by intrinsic and acquired mutations that impact EGFR signal transduction and on the other hand by associated side effects. Thus, there remains a need in the art for EFGR-targeting therapies and methods of their use.

[0006] SGN-EGFRd2 is a bispecific gamma delta (yb)-T cell engager (BS-GDTE) that targets EGFR, a cell surface receptor that is expressed on a variety of solid tumors. Simultaneous binding of EGFR on the tumor cell and the y952-TCR results in the conditional activation of yb-T cells, resulting in release of its cytotoxic molecules and the subsequent death of the tumor cells.

[0007] The unique features of SGN-EGFRd2 and the capabilities of the effector Y952-T cells that it targets are believed to have the potential of making a beneficial impact on the treatment of patients with ORC, HNSCC, NSCLC or PDAC. In the advanced / metastatic setting there is a clear unmet medical need for patients diagnosed with these diseases as the vast majority of patients will experience relapse of disease, become refractory to, or develop resistance to existing therapies and will eventually succumb to the consequences of the disease despite current treatment options.

[0008] In some embodiments, the present disclosure provides a method of treating an EGFR- positive (EGFR+) cancer in a subject in need thereof comprising administering a bispecific gamma delta (yb)-T cell engager (BS-GDTE) comprising a first antigen-binding domain that specifically binds to EGFR and a second antigen-binding domain that binds to human V52, wherein the BS-GDTE is administered at a target dose of at least 5 pg.

[0009] In some embodiments, the BS-GDTE is administered at a target dose of at least 7.5 pg, at least 15 pg, at least 22.5 pg, at least 25 pg, at least 50 pg, at least 75 pg, at least 150 pg, at least 225 pg, at least 450 pg, at least 675 pg, at least 900 pg, at least 1350 pg, at least 1600 pg, at least 1800 pg, at least 2700 pg, at least 3200 pg, or at least 4800 pg.

[0010] In some embodiments, the BS-GDTE is administered twice during a 28-day dosing cycle. In some embodiments, the BS-GDTE is administered three times during a 21-day dosing cycle. In some embodiments, the BS-GDTE is administered once during a 21-day dosing cycle.

[0011] In some embodiments, the BS-GDTE is administered a target dose of about 5 pg, 15 pg, 50 pg, 150 pg, 450 pg, 900 pg, 1800 pg, or 3200 pg and is administered twice during a 28-day dosing cycle. In some embodiments, the first dose of the BS-GDTE is administered on day 1 of the 28-day dosing cycle and wherein the second dose of the BS-GDTE is administered on day 15 of the 28-day dosing cycle.

[0012] In some embodiments, the BS-GDTE is administered a target dose of about 7.5 pg, 25 pg, 75 pg, 225 pg, 450 pg, 900 pg, or 1600 pg and is administered three times during a 21-day dosing cycle. In some embodiments, the first dose of the BS-GDTE is administered on day 1 of the 21-day dosing cycle, the second dose of the BS-GDTE is administered on day 8 of the 21 day dosing cycle, and the third dose of the BS-GDTE is administered on day 15 of the 21-day dosing cycle.

[0013] In some embodiments, the BS-GDTE is administered a target dose of about 22.5 pg, 75 pg, 225 pg, 675 pg, 1350 pg, 2700 pg, or 4800 pg and is administered once during a 21- day dosing cycle. In some embodiments, the BS-GDTE is administered on day 1 of the 21- day dosing cycle.

[0014] In some embodiments, the subject has not received treatment with an aminobisphosphonate. In some embodiments, the subject has received one or more primingdoses of the BS-GDTE. In some embodiments, the one or more priming doses are between 5% and 30% of the target dose.

[0015] In some embodiments, the EGFR+ cancer is selected from colorectal cancer (CRC), head and neck squamous cell cancer (HNSCC), non-small cell lung cancer (NSCLC), and pancreatic ductal adenocarcinoma (PDAC).

[0016] In some embodiments, the cancer is relapsed. In some embodiments, the cancer is refractory to one or more prior treatments.

[0017] In some embodiments, the CRC is unresectable, locally advanced, and / or or metastatic CRC. In some embodiments, the subject has received prior treatment with fluoropyrimidine, oxaliplatin and irinotecan. In some embodiments, the subject has defective mismatch repair and microsatellite instability high (dMMR / MSI-H) In some embodiments, the subject has received prior treatment with an anti-PD-1 agent or anti-PD-L1 agent. In some embodiments, the anti-PD-1 agent is pembrolizumab or nivolumab.

[0018] In some embodiments, the NSCLC is unresectable, locally advanced, and / or or metastatic NSCLC. In some embodiments, the subject has received prior therapy with a platinum-based therapy and at least one anti-PD-1 agent or anti-PD-L1 agent. In some embodiments, the anti-PD-1 agent is pembrolizumab and / or wherein the anti-PD-L1 agent is nivolumab. In some embodiments, the subject has an activating mutation or rearrangement in the EGFR or anaplastic lymphoma kinase (ALK) gene and has received an available targeted agent.

[0019] In some embodiments, the HNSCC is unresectable, locally advanced, and / or or metastatic HNSCC. In some embodiments, the subject has received prior therapy with a platinum-based therapy and at least one anti-PD-1 agent or anti-PD-L1 agent. In some embodiments, the anti-PD-1 agent is pembrolizumab and / or wherein the anti-PD-L1 agent is nivolumab.

[0020] In some embodiments, the PDAC is unresectable, locally advanced, and / or or metastatic PDAC. In some embodiments, the subject has received prior treatment with a gemcitabine- or FOLFIRINOX-based therapy.

[0021] In some embodiments, the first antigen-binding domain of the BS-GDTE comprises a CDR1 of SEQ ID NO: 6, a CDR2 of SEQ ID NO: 7, and a CDR3 of SEQ ID NO: 8, and wherein the second antigen-binding domain of the BS-GDTE comprises a CDR1 of SEQ ID NO: 1 , a CDR2 of SEQ ID NO: 2, and a CDR3 of SEQ ID NO: 3. In some embodiments, the first antigenbinding domain is a VHH domain comprising SEQ ID NO: 9 and wherein the second antigenbinding domain is a VHH domain comprising SEQ ID NO: 4. In some embodiments, the BS- GDTE is a heterodimer comprising a first polypeptide comprising SEQ ID NO: 10 and a second polypeptide comprising SEQ ID NO: 5.DETAILED DESCRIPTION

[0022] The present disclosure provides methods of treating EGFR-positive cancers comprising administering a bispecific gamma delta (yb)-T cell engager (BS-GDTE) comprising a first antigen-binding domain that specifically binds to EGFR and a second antigen-binding domain that binds to human V52. An exemplary BS-GDTE is SGN-EGFRd2, also known as PF-08046052. SGN-EGFRd2 is a bispecific humanized heavy chain-only antibody that binds to both the epidermal growth factor receptor (EGFR) and the V<52 chain of the Vy9V52- T cell receptor (TOR). See WO 2022 / 122973, incorporated herein by reference. Sequences for SGN-EGFRd2 are provided in Table 1 below. The full SGN-EGFRd2 agent is a heterodimer of SEQ ID NO: 5 and SEQ ID NO: 10.

[0023] The unique features of SGN-EGFRd2 and the capabilities of the effector y952-T cells that it targets are believed to have the potential of making a substantial beneficial impact on the treatment of patients with EGFR+ cancer. In some embodiments, the EGFR+ cancer is relapsed / refractory (R / R) colorectal cancer (ORC), head and neck squamous cell cancer (HNSCC), non-small cell lung cancer (NSCLC), or pancreatic ductal adenocarcinoma (PDAC).Table 1 : SGN-EGFRd2 amino acid sequences

[0024] In some embodiments, the first and second antigen-binding domains of the BS-GDTE are VHH domains. The term “VHH,” “VHH antibody,” or “VHH domain” as used herein refers to an antigen-binding domain comprising a single monomeric variable domain (Koch-Nolte, et al, FASEB J., 21 : 3490-3498 (2007)). A VHH comprises three CDRs. In some embodiments, the first antigen-binding domain of the BS-GDTE comprises a CDR1 of SEQ ID NO: 6, a CDR2 of SEQ ID NO: 7, and a CDR3 of SEQ ID NO: 8, and the second antigen-binding domain of the BS-GDTE comprises a CDR1 of SEQ ID NO: 1 , a CDR2 of SEQ ID NO: 2, and a CDR3 of SEQ ID NO: 3. In some embodiments, the first antigen-binding domain is a VHH domain comprising SEQ ID NO: 9 and the second antigen-binding domain is a VHH domain comprising SEQ ID NO: 4. In some embodiments, the BS-GDTE is a heterodimer comprising a first polypeptide comprising SEQ ID NO: 10 and a second polypeptide comprising SEQ ID NO: 5.

[0025] In some embodiments, the BS-GDTE (e.g., SGN-EGFRd2) or a composition thereof is administered at a dose of at least 5 pg, at least 7.5 pg, at least 15 pg, at least 22.5 pg, at least 25 pg, at least 50 pg, at least 75 pg, at least 150 pg, at least 225 pg, at least 450 pg, at least 675 pg, at least 900 pg, at least 1320 pg, at least 1600 pg, at least 1800 pg, at least 2700 pg, at least 3200 pg, or at least 4800 pg. In some embodiments, the BS-GDTE (e.g., SGN- EGFRd2) or a composition thereof is administered to a subject at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, or more times.

[0026] The term “composition” as used herein refers to a formulation of SGN-EGFRd2 that is capable of being administered or delivered to a subject or cell. Typically, formulations include all pharmaceutically acceptable compositions including derivatives and / or prodrugs, solvates, stereoisomers, racemates, or tautomers thereof with any physiologically acceptable carriers, diluents, and / or excipients.

[0027] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0028] As used herein “pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant, and / or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans and / or domestic animals. Exemplary pharmaceutically acceptable carriers include, but are not limited to, to sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth; malt; gelatin; talc; cocoa butter, waxes, animal and vegetable fats, paraffins, silicones, bentonites, silicic acid, zinc oxide; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and any other compatible substances employed in pharmaceutical formulations. Except insofar as any conventional media and / or agent is incompatible with the agents of the present disclosure, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.

[0029] “Pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1 ,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, ptoluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0030] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0031] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0032] Further guidance regarding formulations that are suitable for various types of administration can be found in Remington’s Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17thed. (1985). For a brief review of methods for drug delivery, see, Langer, Science 249:1527-1533 (1990).

[0033] Administration of SGN-EGFRd2 or a composition thereof can occur by injection, irrigation, inhalation, consumption, electro-osmosis, hemodialysis, iontophoresis, and othermethods known in the art. In some embodiments, administration route is local or systemic. In some embodiments administration route is intraarterial, intracranial, intradermal, intraduodenal, intramammary, intrameningeal, intraperitoneal, intrathecal, intratumoral, intravenous, intravitreal, ophthalmic, parenteral, spinal, subcutaneous, ureteral, urethral, vaginal, or intrauterine.

[0034] The BS-GDTE or a composition thereof described herein may be administered according to a suitable dosing interval. Herein, a “dosing interval” refers to the frequency of administration of a particular agent (e.g., the frequency of administration of a BS-GDTE) during the course of treatment.

[0035] The BS-GDTE (e.g., SGN-EGFRd2) or a composition thereof may be administered with any suitable dosing interval, for example a dosing interval of 1 day to 1 month, for example a dosing interval of 1 to 21 days, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days or a dose interval of between 7 and 21 days, such as 7 or 14 days. In some embodiments, the dosing interval of the BS-GDTE or a composition thereof is 7 days. In some embodiments, the dosing interval of the BS-GDTE or a composition thereof is 14 days. In some embodiments, the dosing interval of the BS-GDTE or a composition thereof is 21 days. In some embodiments, the dosing interval of the BS-GDTE is 28 days.

[0036] The BS-GDTE (e.g., SGN-EGFRd2) or a composition thereof described herein may be administered over the course of one or more treatment cycles. Herein, a “treatment cycle” refers to a period of treatment (e.g., administration of a BS-GDTE or a composition thereof) optionally followed by a period of rest (e.g., wherein no therapeutic agents are administered). A full course of treatment may comprise one or more treatment cycles, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, or more treatment cycle. A treatment cycle may be 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more days long. In some embodiments, a treatment cycle is 21 days. In some embodiments, a treatment cycle is 28 days.

[0037] In some embodiments, the treatment cycle is 28 days, with a BS-GDTE (e.g., SGN- EGFRd2) or a composition thereof administered once, twice, or three times during the 28-day cycle. In some embodiments, the treatment cycle is 28 days, with a BS-GDTE (e.g., SGN- EGFRd2) or a composition thereof administered twice during the 28-day cycle. In some such embodiments, the BS-GDTE (e.g., SGN-EGFRd2) or a composition thereof is administered on day 1 and day 15 of the treatment cycle. In some such embodiments, the dose of SGN- EGFRd2 is 5 pg. In some such embodiments, the dose of SGN-EGFRd2 is 15 pg. In some such embodiments, the dose of SGN-EGFRd2 is 50 pg. In some such embodiments, the dose of SGN-EGFRd2 is 150 pg. In some such embodiments, the dose of SGN-EGFRd2 is 450 pg. In some such embodiments, the dose of SGN-EGFRd2 is 900 pg. In some such embodiments,the dose of SGN-EGFRd2 is 1800 g. In some such embodiments, the dose of SGN-EGFRd2 is 3200 pg.

[0038] In some embodiments, the treatment cycle is 21 days, with a BS-GDTE (e.g., SGN- EGFRd2) or a composition thereof administered once, twice, or three times during the 21-day cycle. In some embodiments, the treatment cycle is 21 days, with a BS-GDTE (e.g., SGN- EGFRd2) or a composition thereof administered three times during the 21-day cycle. In some such embodiments, the BS-GDTE (e.g., SGN-EGFRd2) or a composition thereof is administered on day 1 , 8, and 15 of the treatment cycle. In some such embodiments, the dose of SGN-EGFRd2 is 7.5 pg. In some such embodiments, the dose of SGN-EGFRd2 is 25 pg. In some such embodiments, the dose of SGN-EGFRd2 is 75 pg. In some such embodiments, the dose of SGN-EGFRd2 is 225 pg. In some such embodiments, the dose of SGN-EGFRd2 is 450 pg. In some such embodiments, the dose of SGN-EGFRd2 is 900 pg. In some such embodiments, the dose of SGN-EGFRd2 is 1600 pg.

[0039] In some embodiments, the treatment cycle is 21 days, with a BS-GDTE (e.g., SGN- EGFRd2) or a composition thereof administered once during the 21-day cycle. In some embodiments, the treatment cycle is 21 days, with a BS-GDTE (e.g., SGN-EGFRd2) or a composition thereof administered on day 1 of the treatment cycle. In some such embodiments, the dose of SGN-EGFRd2 is 22.5 pg. In some such embodiments, the dose of SGN-EGFRd2 is 75 pg. In some such embodiments, the dose of SGN-EGFRd2 is 225 pg. In some such embodiments, the dose of SGN-EGFRd2 is 675 pg. In some such embodiments, the dose of SGN-EGFRd2 is 1350 pg. In some such embodiments, the dose of SGN-EGFRd2 is 2700 pg. In some such embodiments, the dose of SGN-EGFRd2 is 4800 pg.

[0040] Exemplary treatment regimens are provided below in Table B of the Examples.

[0041] In order to mitigate the risk of cytokine release syndrome (CRS), a step dosing approach can be used. Cytokine release syndrome (CRS) is a systemic inflammatory response that can be triggered by immunotherapeutic agents, such as T-cell-engaging bispecific antibodies. CRS events typically occur in the first treatment cycle with the greatest level of cytokine production often observed after the first dose of the antibody. Step dosing involves administering one or more priming doses of a BS-GDTE prior to the target dose. The priming dose is a lower dose of the BS-GDTE than the target dose. This allows the immune system to be primed in a stepwise manner in an effort to prevent an uncontrolled inflammatory response at the target dose (Ball et al, 2023).

[0042] Accordingly, the term “priming dose” or as used herein refers to a dose of a BS-GDTE described herein that primes a subject for administration of a target dose of the BS-GDTE such that the target dose does not result in one or more therapy-related toxicities such as CRS. A “target dose” as used herein refers to the therapeutically effective dose of a BS-GDTE described herein.

[0043] In some embodiments, the priming dose is 25% or less of the target dose. For example, if a target dose of a BS-GDTE is 100mg, the priming dose would be 25mg. In some embodiments, the priming dose is 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, or 5% or less of the target dose. In some embodiments, the priming dose is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% of the target dose. In some embodiments, the priming dose is 15% of the target dose.

[0044] In some embodiments, the first treatment cycle comprises administration of one or more priming doses and one or more target doses. In some embodiments, the first treatment cycle comprises administration of two priming doses and one or more target doses. In some embodiments, the first treatment cycle comprises administration of three priming doses and one or more target doses. In some embodiments, the first treatment cycle comprises administration of one priming dose and one target dose. In some embodiments, the first treatment cycle comprises administration of two priming doses and one target dose. In some embodiments, the first treatment cycle comprises administration of three priming doses and one target dose.

[0045] In some embodiments, the second treatment cycle comprises administration of one or more priming doses and one or more target doses. In some embodiments, the second treatment cycle comprises administration of two priming doses and one or more target doses. In some embodiments, the second treatment cycle comprises administration of three priming doses and one or more target doses. In some embodiments, the second treatment cycle comprises administration of one priming dose and one target dose. In some embodiments, the second treatment cycle comprises administration of two priming doses and one target dose. In some embodiments, the second treatment cycle comprises administration of three priming doses and one target dose.

[0046] In some embodiments, the first and second treatment cycles comprise administration of one or more priming doses and one or more target doses. In some embodiments, the first and second treatment cycles comprise administration of one priming dose and one or more target doses. In some embodiments, the first and second treatment cycles comprise administration of two priming doses and one or more target doses. In some embodiments, the first and second treatment cycles comprise administration of three priming doses and one or more target doses. In some embodiments, the first and second treatment cycles comprise administration of one priming dose and one target dose. In some embodiments, the first and second treatment cycles comprise administration of two priming doses and one target dose. In some embodiments, the first and second treatment cycles comprise administration of three priming doses and one target dose.

[0047] In some embodiments, the present disclosure provides a method of treating an EGFR+ cancer in a subject in need thereof comprising administering one or more target doses of SGN- EGFRd2 to the subject. In some embodiments, the EGFR+ cancer is relapsed. “Relapsed” as used herein refers to a cancer that has previously responded to treatment and has recurred in the subject. In some embodiments, the EGFR+ cancer is refractory to a prior treatment. “Refractory” as used herein refers to a cancer that does not respond to a particular treatment.

[0048] In some embodiments, the EGFR+ cancer is colorectal cancer (CRC). In some embodiments, the CRC is unresectable, locally advanced, or metastatic. In some embodiments, the subject has received prior therapy with fluoropyrimidine, oxaliplatin and irinotecan. In some embodiments, subjects with defective mismatch repair and microsatellite instability high (dMMR / MSI-H) have received prior treatment with an anti-PD-1 agent or an anti-PD-L1 agent. In some embodiments, the anti-PD-1 agent is an antibody is selected from pembrolizumab (Keytruda®), nivolumab (Opdivo®), Zynz™ (retifanlimab), and Jemperli™ (dostarlimuab). In some embodiments, the anti-PD-L1 agent is antibody is selected from cemiplimab (Libtayo®), atezoliumab (Tecentriq®), Imfinzi® (durvalumab), and Bavencio® (avelumab).

[0049] In some embodiments, the EGFR+ cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is unresectable, locally advanced, or metastatic. In some embodiments, the subject has received prior therapy with a platinum-based therapy and at least one anti-PD-1 and / or anti-PD-L1 agent. In some embodiments, subjects with an activating mutation or rearrangement in the EGFR or anaplastic lymphoma kinase (ALK) gene have received available targeted agents if eligible by biomarker status and local standard of care.

[0050] In some embodiments, the EGFR+ cancer is head and neck squamous cell cancer (HNSCC). In some embodiments, the HNSCC is unresectable, locally advanced, or metastatic HNSCC. In some embodiments, the subject has received prior therapy with a platinum-based therapy and an anti-PD-1 and / or anti-PD-L1 agent, if eligible by biomarker status and local standard of care

[0051] In some embodiments, the EGFR+ cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the PDAC is unresectable, locally advanced, or metastatic. In some embodiments, the subject has received prior therapy with gemcitabine- or FOLFIRINOX-based therapy.EXAMPLESExample 1: A Phase 1 Study of SGN-EGFRd2 in Advanced Solid Tumors

[0052] A phase 1 , open-label, multicenter study is designed to evaluate the safety, tolerability, PK, pharmacodynamics, and antitumor activity of SGN-EGFRd2 in adults with select advanced solid tumors.

[0053] The study will be conducted in 3 parts:(a) Dose escalation (Part A) - Subjects will be treated to evaluate the safety and tolerability of SGN-EGFRd2 to identify the maximum tolerated dose (MTD), and to identify a recommended dose and schedule. Subjects in Part A may have CRC, NSCLC, or HNSCC;(b) Dose optimization (Part B; optional) - Additional cohorts may be opened for up to 2 tumor types to compare different dosing schedules to optimize each dose and schedule. However, dose optimization may be omitted if there is sufficient evidence to support evaluating a dosing regimen in dose expansion and at least 6 subjects have been dosed at the recommended dose and schedule. Tumor types for Part B will be identified by the sponsor from among those specified in dose escalation (Part A).(c) Dose expansion (Part C) - Subjects will be treated in disease-specific expansion cohorts at the recommended dose to characterize the safety, tolerability, PK, pharmacodynamics, and antitumor activity of SGN-EGFRd2. Tumor types for Part C may include CRC, NSCLC, HNSCC, and PDAC.

[0054] Subjects will receive SGN-EGFRd2 as an intravenous (IV) infusion on Day 1 and Day 15 of a 28 day cycle (Q2W). Alternative dosing schedules may be considered (e.g., Day 1 , Day 8, and Day 15 of a 21-day cycle once a week [Q1W], or Day 1 of a 21-day cycle once every 3 weeks [Q3W]). Step-up dosing (7-day cycle) may be implemented prior to treatment cycles. In Part A, the initial dose level will be 15 pg. Dose escalation will proceed incrementally to a maximum dose of 3200 pg, if tolerated.

[0055] Dosing in Part B, if initiated, will occur at the recommended dose(s) and schedule(s) from Part A. Dosing in Part C will occur at the recommended dose and schedule from Part A and optional Part B. Dosing may be interrupted, reduced, or discontinued during the study if it is determined to be in the best interest of the subject.

[0056] Subjects with advanced solid tumors who are eligible for Parts A and B of this study have relapsed or refractory disease, or are intolerant to standard of care therapies, and in the judgement of the investigator must have no appropriate standard therapy available. As these patients have exhausted currently available therapies, prognosis is poor and represents an area of high unmet medical need.Part A: Dose Escalation Cohorts

[0057] Approximately 75 subjects will be evaluated in Part A.

[0058] Part A will be conducted using the modified toxicity probability interval (mTPI) design (Ji 2010) to evaluate the safety and tolerability and to identify the MTD and / or recommended dose of SGN-EGFRd2. Safety, PK, pharmacodynamics, biomarker analyses, and preliminary antitumor activity may be used to determine a recommended dose and schedule.

[0059] The mTPI method uses a Bayesian model to compute the posterior probabilities of 3 intervals that reflect the relative distance between the toxicity rate of each dose level to the target dose limiting toxicity (DLT) rate. Dosing decision rules are determined for a target DLT rate of 25% with a 5% margin. The 3 intervals will be (0%, 20%), (20%, 30%), and (30%, 100%), and the corresponding dosing decision rules will be:(a) Escalate if the current dose DLT rate is likely <20%,(b) Continue if the current dose DLT rate is likely between 20% and 30%,(c) De-escalate if the current dose DLT rate is likely >30%.

[0060] Dose finding decisions are shown in Table A where “E” represents escalating the dose, “S” represents staying at the same dose, and “D” represents de-escalating the dose. Decision “DU” means that the current dose level may be unacceptable because of high toxicity. A dose will be defined as having unacceptable toxicity if the posterior probability that the DLT rate is higher than 25% is more than 95%.Table A

[0061] Initially SGN-EGFRd2 will be administered on Day 1 and Day 15 of 28-day cycles at the planned doses shown in Table B. The starting dose of SGN-EGFRd2 will be 15 pg. Dose escalation will first proceed by approximately 3-fold increments for 3 steps, and then by approximately 2 fold increments for subsequent steps. Intrasubject dose escalation will not be performed. As clinical experience evolves, alternative approaches to SGN-EGFRd2 administration may be evaluated based on recommendation of the SMC including, but not limited to, body surface area-based or weight-based dosing.Table B: Planned Dose Levels for Initial and Alternative SchedulesInitial Schedule Alternative SchedulesQ2W Q1W Q3WDays 1, 15 Days 1, 8, 15 Day 1(28-day Cycle) (21 -day Cycle) (21 -day Cycle)(gg) (gg) (gg)15a7.5 22.550 25 75150 75 225450 225 675900 450 13501800 900 27003200 1600 4800Q2W=every 2 weeks dosing; Q1 W=every 1 week dosing; Q3W=every 3 weeks dosingaIf 15 pg (dose level 1) is dosed in subjects and not deemed safe due to AEs requiring dose reduction, 5 pg (dose level -1) may be tested.

[0062] The following rule will be applied to Part A: Limit the maximum dose increment to 100% for the next dosing cohort if >1 subject experiences 1 event of Grade > 2 CRS or ICANS during the DLT period.Step-up Dosing Option

[0063] Step-up dosing or priming dose strategies (initial lower dose(s) followed by escalation to the full treatment dose), have been effectively utilized for bispecific CD3-T cell engager antibodies to mitigate drug-related toxicity such as CRS and ICANS (Hosseini 2020; Budde 2022; Carvajal 2022). Addition of a step-up dosing cycle may be explored in Part A. The step- up dose and schedule will be chosen based on the totality of the emerging clinical data (e.g., safety, PK, pharmacodynamics) and at the recommendation of the SMC. Step-up doses may be chosen from the dose levels deemed to be tolerable (e.g., CRS Grade <3; ICANS Grade <3) by the SMC and preferably those that have preliminary encouraging pharmacodynamic or antitumor activity.

[0064] If step-up dosing is implemented, the DLT period will include both the step-up dosing cycle and the first treatment cycle (e.g., the DLT period for a 28-day cycle with a 7-day step- up dosing cycle would be 35 days). Extended 16-hour monitoring will be required after all doses in the step up dosing cycle and the first full treatment dose.

[0065] If step-up dosing is implemented, the following rules will be applied to Part A:(a) Limit the maximum dose increment to 100% for both step-up dose(s) and full treatment dose of the next dosing cohort if >1 subject of a given cohort experiences 1 event of Grade >2 CRS or ICANS during the DLT period.(b) Limit the maximum dose increment to 50% for both step-up dose(s) and full treatment dose of the next dosing cohort if >1 subject of a given cohort experience 2 or more events of Grade >2 CRS or ICANS or one DLT during the DLT period.Alternative Dosing Schedules

[0066] Predicted SGN-EGFRd2 human half-life is approximately 10 days which supports evaluation of once every 2 weeks (Q2W) dosing regimen. With evolving clinical efficacy and safety data, the sponsor may explore alternative dosing schedules. Alternative treatment schedules (see Table C) may be evaluated in Part A. The choice of which schedule(s) to open for enrollment will be made by the sponsor in consultation with the SMC, based on the totality of clinical data.

[0067] The starting dose of any alternative dosing regimen will be selected based on an integrated analysis of observed clinical PK, safety, and efficacy. The starting dose level in an alternative schedule will be no higher, in terms of dose intensity (e.g. pg / week), than the highest dose level of the previous schedule(s) deemed tolerable by the SMC. Totality of clinical data including safety, efficacy, PK, pharmacodynamics, and biomarker data and recommendation of the SMC will be considered for selecting the starting dose of alternative schedules.

[0068] One or more dosing schedules, with or without a step-up dosing cycle, may be evaluated sequentially or in parallel in separate cohorts. The mTPI dose escalation rules will be applied separately to each dosing schedule. The SMC may recommend investigation of lower and / or intermediate dose levels, in which case the mTPI dose escalation rules will continue to be applied.Table C: Initial and Alternative Treatment SchedulesSchedule Description Cycle Length Treatment Days Schedule Intensity (days) Day 1 Day 8 Day 15 (infusions / week) Initial schedule Q2W: Days 1, 15 28 X - X 0.5Alternative Q1W: Days 1, 8, 15 21 X X X 1 schedules Q3W: DAV|21 X - - 0.33Part B: Dose Optimization

[0069] Following Part A, if there is sufficient evidence to support evaluating a dosing regimen in Part C, then Part B may be omitted, provided at least 6 subjects have been dosed at the recommended dose and schedule. Otherwise, Part B will be performed to optimize selected doses and schedules identified in Part A. Up to 40 subjects total may be assigned to Part B in up to 2 different tumor types. The dose may be at or below the MTD. Different dosing schedules may be evaluated in parallel or sequential cohorts.Part C: Expansion Cohorts

[0070] To further characterize the safety, tolerability, PK, and antitumor activity of SGN- EGFRd2, up to approximately 160 additional subjects may be enrolled in Part C. The dose(s), schedule, and tumor types for Part C will be determined by the sponsor in consultation with the SMC and may differ between cohorts.

[0071] Part C may enroll the following cohorts:(a) Disease-specific expansion cohorts: Up to approximately 160 subjects may be assigned to 4 disease-specific expansion cohorts. Expansion cohorts may each enroll up to approximately 40 subjects in CRC, NSCLC, HNSCC, and PDAC.(b) An interim analysis will be conducted after approximately 20 subjects in each disease-specific cohort are evaluable for response while the enrollment is uninterrupted. A futility assessment will be performed using the predictive probability of success (PPoS) method (Lee 2008) with success being defined as having more than 0.85 posterior probability that the response rate is greater than the background rate. If the estimated PPoS given the interim data is <10%, the sponsor in consultation with the SMC may decide to stop further enrollment of the cohort after careful assessment of the totality of data.Dose limiting Toxicities

[0072] A DLT is defined as any of the following during the DLT-evaluation period unless the adverse event (AE) is clearly determined to be due to an alternate underlying etiology such as complication(s) of the underlying malignancy, intercurrent illness, or an extraneous cause.Grading will be according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0, unless noted:(a) Grade 5 toxicity.(b) > Grade 4 infusion related reaction (IRR)s, or Grade 3 IRR that does not resolve to < Grade 2 within 24 hours with infusion interruption, infusion rate reduction, and / or standard supportive measures. For subjects receiving premedication for IRR, any > Grade 3 IRR will be considered to be a DLT.(c) In the event of a > Grade 3 IRR in > 20% of subjects (i.e. , 2 or more in the first 10 subjects), all subsequent subjects will require premedication and / or modification of infusion approach per the recommendation of the SMC. For subsequent subjects who have received premedication for IRR or modification of infusion, any > Grade 3 IRR will be considered a DLT.(d) Grade 4 anemia or thrombocytopenia.(e) Grade 4 hematologic toxicity (other than anemia / thrombocytopenia) lasting >7 days.(f) Grade 3 CRS per American Society of Transplantation and Cellular Therapy (ASTCT) criteria lasting > 72 hours.(g) Grade 3 neurotoxicity per the ASTCT immune-effector cells associated neurotoxicity syndrome (ICANS) criteria lasting > 72 hours and does not resolve to Grade 1 or less within 2 weeks.(h) > Grade 3 febrile neutropenia.(i) > Grade 3 thrombocytopenia with clinically significant bleeding.(j) > Grade 3 or 4 non-hematologic toxicity (not laboratory) with the following exceptions:(k) Grade 3 fatigue that resolves within 1 week.(l) Grade 3 nausea, vomiting, or diarrhea that resolves within 72 hours, with or without intervention / supportive care.(m) Grade 3 rash that resolves to < Grade 2 within 7 days with antihistamines or topical treatment or therapy equivalent to or less than prednisone 10 mg / day.(n) > Grade 3 electrolyte / non-hematologic laboratory abnormality if:(o) Grade >3 transaminase (alanine aminotransferase [ALT] or aspartate aminotransferase [AST], or both) elevation, unless in the context of CRS lasting <7 days, OR(p) Grade > 3 elevated amylase or lipase levels associated with symptoms or clinical manifestations of pancreatitis, OR(q) The abnormality persists for >72 hours, is clinically complicated, and does not resolve spontaneously or respond to conventional medical interventions OR(r) The abnormality meets the definition of drug-induced liver injury (DILI) as defined by Hy’s law.(s) Dose delay >14 days due to toxicity.Example 2: Inclusion and Exclusion criteria for the Phase 1 study of Example 1

[0073] Subjects are eligible to be included in the study only if all the following criteria are met:(a) Age 18 years or older at the time of consent.(b) Tumor types:(i) For Part A (Dose Escalation): Subjects must have disease that is relapsed, refractory, or be intolerant to standard of care therapies, and in the judgement of the investigator must have no appropriate standard therapy available at the time of enrollment. If a standard therapy is available that has not been administered, the reason that the therapy is not appropriate must be documented. Subjects must have histologically- or cytologically confirmed metastatic or unresectable solid malignancy from one of the following tumor types:(1) CRC(2) NSCLC(3) HNSCC(c) For Part B (Dose Optimization): Subjects must have disease that is relapsed, refractory, or be intolerant to standard of care therapies, and in the judgement of the investigator must have no appropriate standard therapy available at the time of enrollment. If a standard therapy is available that has not been administered, the reason that the therapy is not appropriate must be documented.(i) The tumor type(s) to be enrolled in dose optimization will be identified by the sponsor from among those specified in Part A.(d) For Part C (Disease-Specific Expansion), subjects must have disease that is relapsed or refractory or be intolerant to standard of care therapies as specified below, unless contraindicated:(i) CRC(1 ) Subjects must have unresectable locally advanced or metastatic CRC.(2) Prior therapy: Subjects must have received prior fluoropyrimidine, oxaliplatin and irinotecan. Subjects with defective mismatch repair and microsatellite instability high (dMMR / MSI-H) should have received prior treatment with pembrolizumab, a nivolumab-containing regimen, or other available anti-PD-1 (programmed cell death protein 1) or anti PD-L1 (programmed cell death 1 ligand) agents.(ii) NSCLC(1 ) Subjects must have unresectable locally advanced or metastaticNSCLC.(2) Prior therapy: Subjects must have received platinum-based therapy and at least 1 PD-1 / PD-L1 inhibitor. These agents may have been administered either as single agents or in combination. Subjects with an activating mutation or rearrangement (e.g., EGFR, anaplastic lymphoma kinase [ALK], etc.) must have received available targeted agents if eligible by biomarker status and local standard of care.(iii) HNSCC(1 ) Subjects must have unresectable locally advanced or metastatic HNSCC.(2) Prior therapy: Subjects must have received platinum-based therapy and a PD-1 / PD-L1 inhibitor, if eligible by biomarker status and local standard of care. These agents may have been administered either as single agents or in combination.(iv) PDAC(1 ) Subjects must have unresectable locally advanced or metastatic PDAC.(2) Prior therapy: Subjects must have received gemcitabine- or FOLFIRINOX-based therapy.(e) Subjects should provide archival tumor tissue if available and also agree to biopsies, if medically feasible.(f) An ECOG Performance Status score of 0 or 1 . Refer to ecog- acrin.org / resources / ecog-performance-status for the most recent version of ECOG.(g) Measurable disease at baseline per RECIST 1.1 criteria.(h) The following baseline laboratory data:(i) Absolute neutrophil count (ANC) >1000 / pL.(ii) Hemoglobin (Hgb) >9 g / dL.(iii) Platelet count >50,000 / pL.(iv) Bilirubin <1.5 x upper limit of normal (ULN) or <3 x ULN for subjects with Gilbert’s disease or documented hepatic tumor involvement.(v) Individual estimated glomerular filtration rate (eGFR) >45 mL / min / 1.73 m2 using the Modification of Diet in Renal Disease (MDRD) study equation and multiplying by body surface area as applicable (Section 10.2).(vi) ALT and AST <3 x ULN.(i) Subjects of childbearing potential under the following conditions:(i) Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU / mL or equivalent units of beta human chorionic gonadotropin [ hCG]) result within 7 days prior to the first dose of SGN-EGFRd2. Subjects with false positive results and documented verification that the subject is not pregnant are eligible for participation.(ii) Must agree not to try to become pregnant during the study and for at least 4 months after the final dose of SGN-EGFRd2.(iii) Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 4 months after the final dose of SGN-EGFRd2.(iv) If sexually active in a way that could lead to pregnancy, must consistently use 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective starting at time of informed consent and continuing through at least 4 months after the final dose of SGN-EGFRd2.(j) Subjects who can get someone pregnant under the following conditions:(i) Must agree not to donate sperm starting at time of informed consent and continuing through at least 4 months after the final dose of SGN-EGFRd2.(ii) If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective starting at time of informed consent and continuing through at least 4 months after the final dose of SGN-EGFRd2.(iii) If sexually active with a person who is pregnant or breastfeeding, must consistently use a condom from the time of informed consent and continuing throughout the study period through at least 4 months after the final dose of SGN-EGFRd2.(k) The subject must provide documented informed consent. Subjects with legally authorized representatives who sign consent on their behalf are not permitted to participate.(l) Baseline corrected QT interval (QTc) <480 ms using the Fridericia’s correction formula.

[0074] Exclusion criteria include:(a) Known hypersensitivity to any excipient contained in the drug formulation of SGN-EGFRd2.(b) History of another malignancy within 3 years before the first dose of study treatment, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.(c) Known active central nervous system metastases or leptomeningeal disease. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry after brain metastases treatment, they have no new or enlarging brain metastases, and are off of corticosteroids prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug.(d) Any active or suspected viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study drug. Routine antimicrobial prophylaxis is permitted.(e) Subjects with a positive hepatitis B surface antigen (HBsAg) and / or antihepatitis B core antibody; subjects with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral prophylaxis.(f) Active hepatitis C infection (positive by PCR or on antiviral therapy for hepatitis C within the last 6 months). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.(g) Known to be positive for human immunodeficiency virus (HIV).(h) Unstable cardiovascular function within 3 months prior to first dose of study drug, defined as:(i) symptomatic ischemia, or(ii) uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic agents is excluded; first degree atrioventricular block or asymptomatic left anterior fascicular block / right bundle branch block is not excluded), or(iii) congestive heart failure or cardiac symptoms consistent with New York Heart Association Class lll-IV, or(iv) myocardial infarction.(i) Major surgery within 4 weeks, or minor surgery within 7 days prior to the first dose of study drug. Subjects must have recovered adequately from the toxicity or complications from the surgery prior to starting SGN-EGFRd2. Subjects who have planned major surgery during the treatment period must be excluded from the study.(j) Current therapy with other systemic anti-neoplastic or investigational agents.(k) Chemotherapy, radiotherapy, biologies, and / or other antitumor treatment with immunotherapy that is not completed 4 weeks prior to first dose of study treatment, or within 2 weeks prior to first dose of study treatment if the underlying disease has progressed on treatment.(l) Treatment with an aminobisphosphonate IV (e.g. ibandronate, pamidronate, zoledronate, etc.) within 4 weeks of the first dose of study treatment.(m) Clinically significant lung disease unrelated to underlying malignancy requiring systemic corticosteroid treatment >10 mg daily prednisone or equivalent within 6 months prior to enrollment (e.g., interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or suspected to have such disease during the screening period.(n) Subjects with either of the following:(i) A condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications within 4 weeks of first dose of SGN-EGFRd2 (inhaled, topical, intraocular, intranasal, and intra-articularsteroids are permitted in the absence of active immune disease, and steroid premedication for prevention of hypersensitivity reactions to radiographic contrast is permitted), or(ii) History of known or suspected autoimmune disease (e.g. inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis) or significant autoimmune-related toxicity from prior immune oncology-based therapy (e.g. prior autoimmune colitis, pneumonitis, transaminitis); subjects with vitiligo, controlled type 1 diabetes mellitus, residual hypothyroidism requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.(o) Estimated life expectancy <12 weeks.(p) Live or live attenuated vaccine(s) received within 30 days prior to the first dose of study drug.(q) Subjects with history of thromboembolic phenomena (pulmonary embolism, deep vein thrombosis, stroke, or ischemic attack) within 6 months prior to the first dose of study drug, currently receiving chronic anticoagulation therapy, or with contraindication to treatment for thromboembolism prophylaxis.(r) Other serious underlying medical condition that, in the opinion of the investigator, would impair the subject’s ability to receive or tolerate the planned treatment and follow-up.Example 3: Concomitant Therapy

[0075] Any concomitant medications (including over the counter or prescription medicines, recreational drugs, vitamins and / or herbal supplements, blood products, radiotherapy, vaccines, etc) that the subject is receiving at the time of consent or receives during the study must be recorded along with the reason for use, and dates of administration (including start and stop dates).

[0076] The following therapies are required:(a) G-CSF is required in the following situations:(i) The treatment of febrile neutropenia.(ii) Subjects who experience Grade 4 neutropenia or febrile neutropenia of any grade in any cycle must receive prophylactic G-CSF in all subsequent cycles.(b) The following should be considered if G-CSF is initiated:(i) The administration of G-CSF should be consistent with American Society of Clinical Oncology (ASCO) guidelines and / or local standard of care (Smith 2015).(ii) Prophylactic G-CSF should start 1 to 3 days after SGN-EGFRd2 administration.(iii) If pegfilgrastim is used, administration should not occur within 12 days before or on the day of SGN-EGFRd2 administration.(iv) If daily G-CSF is used, administration should not occur within 24 hours prior to or on the day of SGN-EGFRd2 administration; if given for the treatment of neutropenia, should continue until the ANC is >1000 / pL (< Grade 2).

[0077] The following therapies are prohibited:(a) Subjects may not receive treatment with an aminobisphosphonate IV (e.g. ibandronate, pamidronate, zoledronate, etc.).(b) Live or live-attenuated vaccines should not be administered within 30 days prior to first dose of study drug and for the duration of study treatment.

[0078] The following therapies are allowed:(a) The use of platelet and / or red blood cell supportive growth factors or transfusions when applicable is allowed. The use of colony stimulating factors for the treatment of neutropenia per institutional practice is permitted during therapy. During the DLT period in dose escalation, growth factor and transfusion support is discouraged unless medically indicated as this may render the subject not evaluable for DLT assessment.(b) Concomitant prednisone (or equivalent) may be used at a dose of <10 mg / day. Use of non-systemic corticosteroids (e.g., inhaled, topical, intra-nasal, intra-articular, and ophthalmic) are permitted.(c) The use of intermittent high-dose corticosteroid treatment to prevent or manage hypersensitivity reactions (including premedication for known hypersensitivity reactions to contrast for radiographic assessments) may be permitted upon consultation with the medical monitor. Intermittent high-dose corticosteroid treatment for other reasons, including management of immune-related toxicities, may be permitted upon consultation with the medical monitor.(d) The use of antibiotics including prophylactics, when applicable, is allowed.(e) The use of denosumab for prevention of skeletal-related events in subjects with bone metastases, when applicable, is permitted.(f) Concomitant use of medications that are cytochrome P450 (CYP450) substrates with narrow therapeutic index are allowed. Transient increase in cytokines in CD3- T cell engagers have been observed that could suppress CYP450 enzymes and cause drugdrug interactions with CYP450 substrates. Subjects who are receiving CYP450 substrates with narrow therapeutic index concomitantly with SGN-EGFRd2 should be closely monitored for adverse reactions as SGN-EGFRd2 might transiently increase cytokines and consequently suppress CYP450 enzymes.(g) Study treatment may be interrupted by palliative radiotherapy not involving target lesions, upon consultation with the medical monitor. Study treatment should be held for at least 14 days prior to and 14 days following administration of radiation.(h) Routine prophylaxis with vaccines is permitted; any vaccines used may contain only inactivated or non-live microorganisms.(i) The sponsor has conducted a thorough risk assessment for the concomitant use of Coronavirus Disease 2019 (COVID-19) vaccines and has determined that the administration of a COVID 19 vaccine during this trial that does not contain live or attenuated virus is considered a concomitant medication that does not require advice or timing of the vaccine beyond the guidance already outlined in this study protocol. This subject population is at risk for severe COVID-19 disease and therefore will benefit from administration of a vaccine that prevents severe disease.(j) Routine premedication for infusion reactions should not be administered prior to the first dose of SGN-EGFRd2. However, subjects who experience IRRs may receive subsequent treatment with premedication. As clinical experience with SGN-EGFRd2 infusion evolves, routine premedication prior to the first dose of SGN-EGFRd2 may be instituted as recommended or required by the SMC.

Claims

CLAIMS1. A method of treating an EGFR-positive (EGFR+) cancer in a subject in need thereof comprising administering a bispecific gamma delta (yb)-T cell engager (BS-GDTE) comprising a first antigen-binding domain that specifically binds to EGFR and a second antigen-binding domain that binds to human V52, wherein the BS-GDTE is administered at a target dose of at least 5 pg.

2. The method of claim 1 , wherein the BS-GDTE is administered at a target dose of at least 7.5 pg, at least 15 pg, at least 22.5 pg, at least 25 pg, at least 50 pg, at least 75 pg, at least 150 pg, at least 225 pg, at least 450 pg, at least 675 pg, at least 900 pg, at least 1350 pg, at least 1600 pg, at least 1800 pg, at least 2700 pg, at least 3200 pg, or at least 4800 pg.

3. The method of claim 1 or claim 2, wherein the BS-GDTE is administered twice during a 28-day dosing cycle.

4. The method of claim 1 or claim 2, wherein the BS-GDTE is administered three times during a 21 -day dosing cycle.

5. The method of claim 1 or claim 2, wherein the BS-GDTE is administered once during a 21-day dosing cycle.

6. The method of claim 1 or claim 2, wherein the BS-GDTE is administered a target dose of about 5 pg, 15 pg, 50 pg, 150 pg, 450 pg, 900 pg, 1800 pg, or 3200 pg and is administered twice during a 28-day dosing cycle.

7. The method of claim 3 or claim 6, wherein the first dose of the BS-GDTE is administered on day 1 of the 28-day dosing cycle and wherein the second dose of the BS- GDTE is administered on day 15 of the 28-day dosing cycle.

8. The method of claim 1 or claim 2, wherein the BS-GDTE is administered a target dose of about 7.5 pg, 25 pg, 75 pg, 225 pg, 450 pg, 900 pg, or 1600 pg and is administered three times during a 21-day dosing cycle.

9. The method of claim 4 or claim 8, wherein the first dose of the BS-GDTE is administered on day 1 of the 21-day dosing cycle, the second dose of the BS-GDTE is administered on day 8 of the 21 day dosing cycle, and the third dose of the BS-GDTE is administered on day 15 of the 21-day dosing cycle.

10. The method of claim 1 or claim 2, wherein the BS-GDTE is administered a target dose of about 22.5 pg, 75 pg, 225 pg, 675 pg, 1350 pg, 2700 pg, or 4800 pg and is administered once during a 21-day dosing cycle.

11. The method of claim 5 or claim 10, wherein the BS-GDTE is administered on day 1 of the 21 -day dosing cycle.

12. The method of any one of claims 1-11 , wherein the subject has not received treatment with an aminobisphosphonate.

13. The method of any one of claims 1-12, wherein the subject has received one or more priming doses of the BS-GDTE.

14. The method of claim 13, wherein the one or more priming doses are between 5% and 30% of the target dose.

15. The method of any one of claims 1-14, wherein the EGFR+ cancer is selected from colorectal cancer (CRC), head and neck squamous cell cancer (HNSCC), non-small cell lung cancer (NSCLC), and pancreatic ductal adenocarcinoma (PDAC).

16. The method of any one of claims 1-15, wherein the cancer is relapsed.

17. The method of any one of claims 1-16, wherein the cancer is refractory to one or more prior treatments.

18. The method of any one of claims 15-17, wherein the CRC is unresectable, locally advanced, and / or or metastatic CRC.

19. The method of any one of claims 15-18, wherein the subject has received prior treatment with fluoropyrimidine, oxaliplatin and irinotecan.

20. The method of any one of claims 15-19, wherein the subject has defective mismatch repair and microsatellite instability high (dMMR / MSI-H).

21. The method of claim 20, wherein the subject has received prior treatment with an anti- PD-1 agent or anti-PD-L1 agent.

22. The method of claim 21 , wherein the anti-PD-1 agent is pembrolizumab or nivolumab.

23. The method of any one of claims 15-17, wherein the NSCLC is unresectable, locally advanced, and / or or metastatic NSCLC.

24. The method of any one of claims 15-17 or claim 23, wherein the subject has received prior therapy with a platinum-based therapy and at least one anti-PD-1 agent or anti-PD-L1 agent.

25. The method of claim 24, wherein the anti-PD-1 agent is pembrolizumab and / or wherein the anti-PD-L1 agent is nivolumab.

26. The method of any one of claims 15-17 or 23-25, wherein the subject has an activating mutation or rearrangement in the EGFR or anaplastic lymphoma kinase (ALK) gene and has received an available targeted agent.

27. The method of any one of claims 15-17, wherein the HNSCC is unresectable, locally advanced, and / or or metastatic HNSCC.

28. The method of any one of claims 15-17 or claim 27, wherein the subject has received prior therapy with a platinum-based therapy and at least one anti-PD-1 agent or anti-PD-L1 agent.

29. The method of claim 28, wherein the anti-PD-1 agent is pembrolizumab and / or wherein the anti-PD-L1 agent is nivolumab.

30. The method of any one of claims 15-17, wherein the PDAC is unresectable, locally advanced, and / or or metastatic PDAC.

31. The method of any one of claims 15-17 or claim 30, wherein the subject has received prior treatment with a gemcitabine- or FOLFIRINOX-based therapy.

32. The method of any one of claims 1-31 , wherein the first antigen-binding domain of the BS-GDTE comprises a CDR1 of SEQ ID NO: 6, a CDR2 of SEQ ID NO: 7, and a CDR3 of SEQ ID NO: 8, and wherein the second antigen-binding domain of the BS-GDTE comprises a CDR1 of SEQ ID NO: 1, a CDR2 of SEQ ID NO: 2, and a CDR3 of SEQ ID NO: 3.

33. The method of any one of claims 1-32, wherein the first antigen-binding domain is a VHH domain comprising SEQ ID NO: 9 and wherein the second antigen-binding domain is a VHH domain comprising SEQ ID NO: 4.

34. The method of any one of claims 1-33, wherein the BS-GDTE is a heterodimer comprising a first polypeptide comprising SEQ ID NO: 10 and a second polypeptide comprising SEQ ID NO: 5.

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