Vasconstrictors for reducing ocular toxicity of antibody-maytansinoid conjugates

Abstract

The present disclosure provides methods of administering antibody-maytansinoid conjugates (AMCs) comprising administering an effective amount of the AMC in combination with a vasoconstrictor. Ocular toxicities associated with the AMCs can be significantly reduced, without adversely effecting therapeutic efficacy, using such methods.

Description

VASCONSTRICTORS FOR REDUCING OCULAR TOXICITY OF ANTIBOD Y- MAYTANSINOID CONJUGATESFIELD OF THE DISCLOSURE

[0001] The field of this disclosure generally relates to methods of using a vasoconstrictor, e.g., brimonidine, to reduce ocular toxicity in patients receiving maytansinoid-drug conjugate therapy.CROSS-REFRENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. application no. 63 / 595,394, filed November 2, 2023, which is incorporated herein by reference in its entirety.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALL Y

[0003] The content of the electronically submitted sequence listing (Name: 6776_6501_Sequence_Listing.xml; Size: 50,965 bytes; and Date of Creation: October 31, 2024) filed with the application is incorporated herein by reference in its entirety.BACKGROUND

[0004] Cancer is one of the leading causes of death in the developed world, with over one million people diagnosed with cancer and 500,000 deaths per year in the United States alone. Overall it is estimated that more than 1 in 3 people will develop some form of cancer during their lifetime.

[0005] Antibody-drug conjugates (ADC) composed of highly cytotoxic agents conjugated to antibodies that bind to tumor-associated antigens represent a promising therapeutic strategy to enhance the potency of tumor-targeting antibodies. ADCs offer the potential to combine the favorable pharmacokinetics, biodistribution, and tumor-targeting properties of antibodies with the potent cell killing mechanism provided by the attached small molecule, or payload.

[0006] One promising group of ADCs are those that contain maytansinoid drugs. Maytansinoids are a class of microtubule-targeted drugs with potent anti-mitotic activity that were derived from a naturally occurring maytansine. While maytansine demonstrated only a small therapeutic window due to neurotoxicity and to adverse effects on the gastrointestinal tract, ADCs containing maytansinoids have shown promising clinical results. Indeed, an ADC containing the maytansinoid DM4 (ELAHERE®; mirvetuximab soravtansine) was approved by the U.S. Food and Drug Administration in 2022 for the treatment of adult patients with folate receptor alpha (FRa) positive, platinum-resistant epithelial ovarian, fallopian tube, orprimary peritoneal cancer, who have received one to three prior systemic treatment regimens. Additional ADCs containing maytansinoids are currently in clinical and pre-clinical studies aimed at the development of additional cancer therapeutics.

[0007] However, ADCs containing maytansinoids have been associated with reversible ocular adverse events. The mechanism that results in these ocular adverse events is not understood, particularly in light of the fact that they can be associated with ADCs directed against an antigen that is not expressed in the eye (e.g., FRa). Methods of decreasing such ocular adverse events, including administering such ADCs based on a patient’s adjusted ideal body weight (AIBW) instead of based on the patient’s total body weight, have been identified. However, some patients still experience ocular toxicities. In view of the fact that even reversible ocular adverse events are undesirable as they can diminish patient’s quality of life and disrupt therapy, there remains a need to further decrease ocular adverse events in patients receiving ADCs containing maytansinoids.SUMMARY OF THE DISCLOSURE

[0008] Provided herein are methods of using vasoconstrictors, such as brimonidine, to reduce ocular toxicity in patients receiving ADCs containing maytansinoids.

[0009] For example, provided herein is a method of administering an antibody maytansinoid conjugate (AMC) to a patient in need thereof comprising administering an effective amount of a vasoconstrictor and an effective amount of the AMC to the patient, wherein the vasoconstrictor is administered after the AMC is administered. In some aspects, the method reduces ocular toxicity. In some aspects, the method treats ocular toxicity.

[0010] Also provided herein is a method of reducing ocular toxicity associated with the administration of an AMC to a patient, the method comprising administering an effective amount of a vasoconstrictor to the patient after the patient has been treated with the AMC. Also provided herein is a method of treating ocular toxicity associated with the administration of an AMC to a patient, the method comprising administering an effective amount of a vasoconstrictor to the patient after the patient has been treated with the AMC. In some aspects, the method further comprises administering the AMC to the patient prior to administering the effective amount of the vasoconstrictor to the patient.

[0011] In some aspects, the vasoconstrictor is administered on at least three days after administration of the AMC, optionally where the at least three days are the three consecutive days after the administration of the vasoconstrictor. In some aspects, the vasoconstrictor is administered on at least four days after administration of the AMC, optionally where the atleast four days are the four consecutive days after the administration of the vasoconstrictor. In some aspects, the vasoconstrictor is administered on at least four days after administration of the AMC, optionally where the at least four days are the four consecutive days after the administration of the vasoconstrictor. In some aspects, the vasoconstrictor is administered on at least five days after administration of the AMC, optionally where the at least five days are the five consecutive days after the administration of the vasoconstrictor. In some aspects, the vasoconstrictor is administered on at least six days after administration of the AMC, optionally where the at least six days are the six consecutive days after the administration of the vasoconstrictor. In some aspects, the vasoconstrictor is administered on at least seven days after administration of the AMC, optionally where the at least seven days are the seven consecutive days after the administration of the vasoconstrictor. In some aspects, the vasoconstrictor is administered on at least seven days after administration of the AMC, optionally where the at least seven days are the seven consecutive days after the administration of the vasoconstrictor. In some aspects, the vasoconstrictor is administered on at least fourteen days after administration of the AMC, optionally where the at least fourteen days are the fourteen consecutive days after the administration of the vasoconstrictor. In some aspects, the vasoconstrictor is administered on at least twenty-one days after administration of the AMC, optionally where the at least twenty-one days are the twenty-one consecutive days after the administration of the vasoconstrictor. In some aspects, the vasoconstrictor is administered on at least twenty-eight days after administration of the AMC, optionally where the at least twentyeight days are the twenty-eight consecutive days after the administration of the vasoconstrictor.

[0012] In some aspects, the AMC is administered once every three weeks. In some aspects, the vasoconstrictor is administered at least once a day throughout the three weeks. In some aspects, the vasoconstrictor is administered on the seven consecutive days after the administration of the vasoconstrictor, but is not administered on the following fourteen days. In some aspects, the vasoconstrictor is administered on the fourteen consecutive days after the administration of the vasoconstrictor, but is not administered on the following seven days.

[0013] In some aspects, the AMC is administered once every four weeks. In some aspects, the vasoconstrictor is administered at least once a day throughout the four weeks. In some aspects, the vasoconstrictor is administered on the seven consecutive days after the administration of the vasoconstrictor, but is not administered on the following twenty-one days. In some aspects, the vasoconstrictor is administered on the fourteen consecutive days after the administration of the vasoconstrictor, but is not administered on the following fourteen days.In some aspects, the vasoconstrictor is administered on the twenty-one consecutive days after the administration of the vasoconstrictor, but is not administered on the following seven days.

[0014] In some aspects, the vasoconstrictor is also administered prior to administration of the AMC and / or at the same time as administration of the AMC.

[0015] In some aspects, the vasoconstrictor is also administered immediately prior to the administration of the AMC. In some aspects, the vasoconstrictor is administered immediately after the administration of the AMC.

[0016] In some aspects, the vasoconstrictor is administered three times per day. In some aspects, the vasoconstrictor is administered twice per day. In some aspects, the vasoconstrictor is administered once daily. In some aspects, In some aspects, the vasoconstrictor is administered four times per day.

[0017] In some aspects, the vasoconstrictor is administered once per day to five times per day. In some aspects, In some aspects, the vasoconstrictor is administered as an eye drop. IN some aspects, the eye drop is refrigerated.

[0018] In some aspects, the vasoconstrictor is selected from the group consisting of brimonidine, apraclonidine, dipivefrin, epinephrine, naphazoline, phenylephrine, oxymetazoline, tetryzoline, and combinations thereof. In some aspects, the vasoconstrictor is an alpha-2 adrenergic receptor agonist. In some aspects, the vasoconstrictor is brimonidine. In some aspects, the vasoconstrictor is brimonidine tartrate. In some aspects, wherein the vasoconstrictor is brimonidine tartrate 0.1-0.2%.

[0019] In some aspects, the ocular toxicity is Grade 2 or higher ocular toxicity. In some aspects, the ocular toxicity is Grade 3 or higher ocular toxicity. In some aspects, the ocular toxicity is dry eye, blurred vision, comeal keratopathy, comeal microcysts, comeal edema, and / or comeal haze. In some aspects, the ocular toxicity is a comeal condition or disorder. In some aspects, the comeal condition or disorder is punctate keratitis, confluent keratitis, keratopathy, confluent keratopathy, cornea epithelial defect, comeal ulcer, cornea stromal opacity, comeal perforation, or any combination thereof. In some aspects, the ocular toxicity does not comprise cornea stromal opacity or cornea subepithelial opacity.

[0020] In some aspects, the maytansinoid is DM1. In some aspects, the maytansinoid is DM4. In some aspects, the maytansinoid is DM21.

[0021] In some aspects, the AMC comprises an antibody or antigen-binding fragment thereof binds to FRa. In some aspects, the antibody or antigen-binding fragment thereof that binds to FRa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24 and / or a light chain variable region comprising the amino acid sequence ofSEQ ID NO:27. In some aspects, the antibody or antigen-binding fragment thereof that binds to FRa is a biparatopic antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24, a light chain variable region comprising the amino acid sequence of SEQ ID NO:27, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:26.

[0022] In some aspects, the AMC comprises an antibody or antigen-binding fragment thereof binds to ADAM9. In some aspects, the antibody or antigen-binding fragment thereof that binds to ADAM9 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO:28.

[0023] In some aspects, the AMC comprises an IgG antibody or antigen-binding fragment. In some aspects, the AMC comprises an IgGl antibody or antigen-binding fragment. In some aspects, the AMC comprises an antibody comprising a human IgGl constant region.

[0024] In some aspects, the AMC comprises an antibody or antigen-binding fragment thereof linked to a maytansinoid through the s-amino group of a lysine residue of the antibody or antigen-binding fragment thereof. In some aspects, the AMC comprises an antibody or antigen-binding fragment thereof is linked to the maytansinoid through a Cys thiol group.

[0025] In some aspects, the AMC is IMGN853. In some aspects, the AMC is IMGN151. In some aspects, the AMC is IMGC936.

[0026] In some aspects, the patient has cancer. In some aspects, the cancer is ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, breast cancer, gastroesophageal cancer, colorectal cancer, or pancreatic cancer. In some aspects, the ovarian cancer is epithelial ovarian cancer. In some aspects, the peritoneal cancer is primary peritoneal cancer. In some aspects, the lung cancer is non-squamous non-small cell lung cancer. In some aspects, the breast cancer is triple negative breast cancer.

[0027] In some aspects, the AMC is IMGN853 and the patient has recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In some aspects, the patient has FRa positive platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, and wherein the patient has received one to three prior systemic treatment regimens.

[0028] In some aspects, the AMC is IMGN151 and the patient has recurrent endometrial cancer, recurrent high-grade serous epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer. In some aspects, the patient has FRa positive platinum-resistant epithelial ovarian,fallopian tube, or primary peritoneal cancer, and wherein the patient has received one to three prior systemic treatment regimens.

[0029] In some aspects, the AMC is IMGC936 and the patient has non-squamous nonsmall cell lung cancer, triple-negative breast cancer, gastroesophageal cancer, colorectal cancer, or pancreatic cancer.

[0030] In some aspects, the method further comprises administering a steroid eye drop to the patient. In some aspects, the steroid is prednisolone.

[0031] In some aspects, the method further comprises administering corticosteroid eye drops to the patient.

[0032] In some aspects, the method further comprises administering lubricating eye drops to the patient. In some aspects, the lubricating eye drops are administered after the vasoconstrictor. In some aspects, the lubricating eye drops are administered about 5 minutes to about an hour after the administration of the vasoconstrictor. In some aspects, the lubricating eye drops are administered about 10 minutes to about 30 minutes after the administration of the vasoconstrictor. In some aspects, the lubricating eye drops are administered about 15 minutes after the administration of the vasoconstrictor.

[0033] In some aspects, the patient has ocular symptoms prior to the administration of the vasoconstrictor. In some aspects, the ocular symptoms comprise corneal microsyst-like epithelial keratopathy > Grade 2.

[0034] In some aspects, the patient does not have ocular symptoms prior to the administration of the vasoconstrictor. In some aspects, the patient is at risk of developing ocular symptoms.

[0035] In some aspects, the patient is a human patient.

[0036] Also provided herein is a use of a vasoconstrictor in the manufacture of a medicament for use in any of the methods provided herein. Also provided herein is a use of an AMC in the manufacture of a medicament for use in any method provided herein.

[0037] In some embodiments, the disclosure provides:[Embodiment 1] A method of administering an antibody maytansinoid conjugate (AMC) to a patient in need thereof comprising administering an effective amount of a vasoconstrictor and an effective amount of the AMC to the patient, wherein the vasoconstrictor is administered after the AMC is administered.[Embodiment 2] The method of Embodiment 1, wherein the method reduces ocular toxicity.[Embodiment 3] The method of Embodiment 1 , wherein the method treats ocular toxicity.[Embodiment 4] A method of reducing ocular toxicity associated with the administration of an AMC to a patient, the method comprising administering an effective amount of a vasoconstrictor to the patient after the patient has been treated with the AMC.[Embodiment 5] A method of treating ocular toxicity associated with the administration of an AMC to a patient, the method comprising administering an effective amount of a vasoconstrictor to the patient after the patient has been treated with the AMC.[Embodiment 6] The method of Embodiment 4 or 5, further comprising administering the AMC to the patient prior to administering the effective amount of the vasoconstrictor to the patient.[Embodiment 7] A method for safely and effectively treating of cancer in a patient, wherein the method comprises:(a) intravenously administering a therapeutically effective amount of an AMC to the patient; and(b) topically administering a vasoconstrictor to at least one eye of the patient after the administration of the AMC; wherein when the method is used to treat cancer in a population of patients the method results in a reduction in the frequency of one or more ocular toxicity compared to an identical comparator method practiced without the step of administering the vasoconstrictor.[Embodiment 8] A method for safely and effectively treating of cancer in a patient with an AMC delivered to the patient intravenously, wherein the method comprises: topically administering a vasoconstrictor to at least one eye of the patient after the administration of the AMC; wherein when the method is used to treat cancer in a population of patients the method results in a reduction in the frequency of one or more ocular toxicity compared to an identical comparator method practiced without the step of administering the vasoconstrictor.[Embodiment 9] The method of Embodiment 7 or 8, wherein the comparator method comprises administering a steroid eye drop to at least one eye of the patient before the administration of the AMC.[Embodiment 10] The method of Embodiment 9, wherein the steroid eye drop comprises prednisolone.[Embodiment 11] The method of any one of Embodiments 7 to 10, wherein the method results in a reduction in the frequency of Grade 3 or higher ocular toxicity.[Embodiment 12] The method of any one of Embodiments 7 to 10, wherein the method results in a reduction in the frequency of Grade 2 or higher ocular toxicity.[Embodiment 13] The method of any one of Embodiments 7 to 12, wherein the reduction in frequency is an at least 10%, 20%, 30%, 40% or 50% reduction.[Embodiment 14] The method of any one of Embodiments 7 to 12, wherein the frequency of the one or more ocular toxicity is reduced to less than 40%, 30% 20% or 10%.[Embodiment 15] An improved method for treating cancer in a patient by intravenous administration of an AMC to the patient, the improvement comprising reducing adverse eye toxicity by topically administering a vasoconstrictor to at least one eye of the patient after the administration of the AMC.[Embodiment 16] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least two days after administration of the AMC, optionally where the at least two days are the two consecutive days after the administration of the vasoconstrictor.[Embodiment 17] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least three days after administration of the AMC, optionally where the at least three days are the three consecutive days after the administration of the vasoconstrictor.[Embodiment 18] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least four days after administration of the AMC, optionally where the at least four days are the four consecutive days after the administration of the vasoconstrictor.[Embodiment 19] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least five days after administration of the AMC, optionally where the at least five days are the five consecutive days after the administration of the vasoconstrictor.[Embodiment 20] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least six days after administration of the AMC, optionally where the at least six days are the six consecutive days after the administration of the vasoconstrictor.[Embodiment 21] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least seven days after administration of the AMC, optionally where the at least seven days are the seven consecutive days after the administration of the vasoconstrictor.[Embodiment 22] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least eight days after administration of the AMC,optionally where the at least eight days are the eight consecutive days after the administration of the vasoconstrictor.[Embodiment 23] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least fourteen days after administration of the AMC, optionally where the at least fourteen days are the fourteen consecutive days after the administration of the vasoconstrictor.[Embodiment 24] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least twenty-one days after administration of the AMC, optionally where the at least twenty-one days are the twenty-one consecutive days after the administration of the vasoconstrictor.[Embodiment 25] The method of any one of Embodiments 1-15, wherein the vasoconstrictor is administered on at least twenty-eight days after administration of the AMC, optionally where the at least twenty-eight days are the twenty-eight consecutive days after the administration of the vasoconstrictor.[Embodiment 26] The method of any one of Embodiments 1-25, wherein the AMC is administered once every three weeks.[Embodiment 27] The method of Embodiment 26, wherein the vasoconstrictor is administered at least once a day throughout the three weeks.[Embodiment 28] The method of Embodiment 26, wherein the vasoconstrictor is administered on the seven consecutive days after the administration of the vasoconstrictor, but is not administered on the following fourteen days.[Embodiment 29] The method of Embodiment 26, wherein the vasoconstrictor is administered on the fourteen consecutive days after the administration of the vasoconstrictor, but is not administered on the following seven days.[Embodiment 30] The method of any one of Embodiments 1-25, wherein the AMC is administered once every four weeks.[Embodiment 31] The method of Embodiment 30, wherein the vasoconstrictor is administered at least once a day throughout the four weeks.[Embodiment 32] The method of Embodiment 30, wherein the vasoconstrictor is administered on the seven consecutive days after the administration of the vasoconstrictor, but is not administered on the following twenty-one days.[Embodiment 33] The method of Embodiment 30, wherein the vasoconstrictor is administered on the fourteen consecutive days after the administration of the vasoconstrictor, but is not administered on the following fourteen days.[Embodiment 34] The method of Embodiment 30, wherein the vasoconstrictor is administered on the twenty-one consecutive days after the administration of the vasoconstrictor, but is not administered on the following seven days.[Embodiment 35] The method of any one of Embodiments 1-34, wherein the vasoconstrictor is also administered prior to administration of the AMC, and / or at the same time as administration of the AMC.[Embodiment 36] The method of any one of Embodiments 1-35, wherein the vasoconstrictor is also administered immediately prior to the administration of the AMC. [Embodiment 37] The method of any one of Embodiments 1-36, wherein the vasoconstrictor is administered immediately after the administration of the AMC. [Embodiment 38] The method of any one of Embodiments 1-37, wherein the vasoconstrictor is administered three times per day. [Embodiment 39] The method of any one of Embodiments 1-37, wherein the vasoconstrictor is administered twice per day. [Embodiment 40] The method of any one of Embodiments 1-37, wherein the vasoconstrictor is administered once daily. [Embodiment 41] The method of any one of Embodiments 1-37, wherein the vasoconstrictor is administered four times per day. [Embodiment 42] The method of any one of Embodiments 1-37, wherein the vasoconstrictor is administered once per day to five times per day. [Embodiment 43] The method of any one of Embodiments 1-42, wherein the vasoconstrictor is administered as an eye drop, optionally wherein the eye drop is refrigerated.[Embodiment 44] The method of any one of Embodiments 1-43, wherein the vasoconstrictor is selected from the group consisting of brimonidine, apraclonidine, dipivefrin, epinephrine, naphazoline, phenylephrine, oxymetazoline, tetryzoline, and combinations thereof.[Embodiment 45] The method of any of Embodiments 1-44, wherein the vasoconstrictor is an alpha-2 adrenergic receptor agonist.[Embodiment 46] The method of any one of Embodiments 1-45, wherein the vasoconstrictor is brimonidine.[Embodiment 47] The method of Embodiment 46, wherein the vasoconstrictor is brimonidine tartrate.[Embodiment 48] The method of Embodiment 47, wherein the vasoconstrictor is brimonidine tartrate 0.1-0.2%.[Embodiment 49] The method of Embodiment 48, wherein the vasoconstrictor comprises 0.2% w / v brominidine tartrate.[Embodiment 50] The method of Embodiment 48, wherein the vasoconstrictor comprises 0.15% w / v brominidine tartrate.[Embodiment 51] The method of Embodiment 48, wherein the vasoconstrictor comprises 0.1% w / v brominidine tartrate.[Embodiment 52] The method of any one of Embodiments 2-51, wherein the ocular toxicity is Grade 2 or higher ocular toxicity.[Embodiment 53] The method of any one of Embodiments 2-51, wherein the ocular toxicity is Grade 3 or higher ocular toxicity.[Embodiment 54] The method of any one of Embodiments 2-53, wherein the ocular toxicity is dry eye, blurred vision, comeal keratopathy, comeal microcysts, comeal edema, and / or comeal haze.[Embodiment 55] The method of any one of Embodiments 2-53, wherein the ocular toxicity is a comeal condition or disorder.[Embodiment 56] The method of Embodiment 55, wherein the comeal condition or disorder is punctate keratitis, confluent keratitis, keratopathy, confluent keratopathy, cornea epithelial defect, comeal ulcer, cornea stromal opacity, comeal perforation, or any combination thereof.[Embodiment 57] The method of any one of Embodiments 2-56, wherein the ocular toxicity does not comprise cornea stromal opacity or cornea subepithelial opacity. [Embodiment 58] The method of any one of Embodiments 1-57, wherein the maytansinoid is DM1.[Embodiment 59] The method of any one of Embodiments 1-57, wherein the maytansinoid is DM4 .[Embodiment 60] The method of any one of Embodiments 1-57, wherein the maytansinoid is DM21.[Embodiment 61] The method of any one of Embodiments 1-60, wherein the AMC comprises an antibody or antigen-binding fragment thereof that binds to FRa.[Embodiment 62] The method of Embodiment 61 , wherein the antibody or antigen-binding fragment thereof that binds to FRa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24 and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO:27.[Embodiment 63] The method of Embodiment 61, wherein the antibody or antigen-binding fragment thereof that binds to FRa is a biparatopic antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 24, a light chain variable region comprising the amino acid sequence of SEQ ID NO:27, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:26.[Embodiment 64] The method of any one of Embodiments 1-60, wherein the AMC comprises an antibody or antigen-binding fragment thereof that binds to ADAM9.[Embodiment 65] The method of Embodiment 64 wherein the antibody or antigen-binding fragment thereof that binds to ADAM9 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO:28.[Embodiment 66] The method of any one of Embodiments 1-65, wherein the AMC comprises an IgG antibody or antigen-binding fragment.[Embodiment 67] The method of any one of Embodiments 1-66, wherein the AMC comprises an IgGl antibody or antigen-binding fragment.[Embodiment 68] The method of any one of Embodiments 1-67, wherein the AMC comprises an antibody comprising a human IgGl constant region. [Embodiment 69] The method of any one of Embodiments 1-68, wherein the AMC comprises an antibody or antigen-binding fragment thereof linked to a maytansinoid through the a-amino group of a lysine residue of the antibody or antigen-binding fragment thereof.[Embodiment 70] The method of any one of Embodiments 1-68, wherein the AMC comprises an antibody or antigen-binding fragment thereof is linked to the maytansinoid through a Cys thiol group.[Embodiment 71] The method of any one of Embodiments 1-57, wherein the AMC is IMGN853.[Embodiment 72] The method of any one of Embodiments 1-57, wherein the AMC isIMGN151.[Embodiment 73] The method of any one of Embodiments 1-57, wherein the AMC isIMGC936.[Embodiment 74] The method of any one of Embodiments 1-73, wherein the patient has cancer.[Embodiment 75] The method of Embodiment 74, wherein the cancer is ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, breast cancer, gastroesophageal cancer, colorectal cancer, or pancreatic cancer.[Embodiment 76] The method of Embodiment 74, wherein the ovarian cancer is epithelial ovarian cancer.[Embodiment 77] The method of Embodiment 74, wherein the peritoneal cancer is primary peritoneal cancer. [Embodiment 78] The method of Embodiment 74, wherein the lung cancer is nonsquamous non-small cell lung cancer.[Embodiment 79] The method of Embodiment 74, wherein the breast cancer is triple negative breast cancer.[Embodiment 80] The method of any one of Embodiments 1-57, wherein the AMC is IMGN853 and the patient has recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.[Embodiment 81] The method of Embodiment 80, wherein the patient has FRa positive platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, and wherein the patient has received one to three prior systemic treatment regimens.[Embodiment 82] The method of Embodiment 80 or 81, wherein IMGN853 is administered at a dose of 6 mg / kg adjusted ideal body weight on day 1 of a three week cycle and brimonidine tartrate is administered three times daily on day 1 to day 8 of the cycle.[Embodiment 83] The method of Embodiment 80 or 81, wherein IMGN853 is administered at a dose of 6 mg / kg adjusted ideal body weight on day 1 of a three week cycle and brimonidine tartrate is administered three times daily on day 1 to day 8 of the cycle, and wherein brimonidine tartrate is administered on day 1 before the administration of IMGN853. [Embodiment 84] The method of any one of Embodiments 1-57, wherein the AMC is IMGN151 and the patient has recurrent endometrial cancer, recurrent high-grade serous epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer.[Embodiment 85] The method of Embodiment 84, wherein the patient has FRa positive platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, and wherein the patient has received one to three prior systemic treatment regimens.[Embodiment 86] The method of any one of Embodiments 1-57, wherein the AMC is IMGC936 and the patient has non-squamous non-small cell lung cancer, triple-negative breast cancer, gastroesophageal cancer, colorectal cancer, or pancreatic cancer.[Embodiment 87] The method of any one of Embodiments 1-86, wherein the method further comprises administering a steroid eye drop to the patient.[Embodiment 88] The method of Embodiment 87, wherein the steroid is prednisolone.[Embodiment 89] The method of any one of Embodiments 1-88, wherein the method further comprises administering a corticosteroid eye drop to the patient.[Embodiment 90] The method of any one of Embodiments 1-89, further comprising administering lubricating eye drops to the patient.[Embodiment 91] The method of Embodiment 90, wherein the lubricating eye drops are administered after the vasoconstrictor.[Embodiment 92] The method of Embodiment 91, wherein the lubricating eye drops are administered about 5 minutes to about an hour after the administration of the vasoconstrictor.[Embodiment 93] The method of Embodiment 92, wherein the lubricating eye drops are administered about 10 minutes to about 30 minutes after the administration of the vasoconstrictor.[Embodiment 94] The method of Embodiment 93, wherein the lubricating eye drops are administered about 15 minutes after the administration of the vasoconstrictor.[Embodiment 95] The method of any one of Embodiments 90-94, wherein the lubricating eye drops are administered four times a day.[Embodiment 96] The method of any one of Embodiments 90-95, wherein the lubricating eye drops are administered on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 28 days after administration of the AMC.[Embodiment 97] The method of any one of Embodiments 90-95, wherein the lubricating eye drops are administered on every day of the treatment cycle.[Embodiment 98] The method of any one of Embodiments 1-97, wherein the patient has ocular symptoms prior to the administration of the vasoconstrictor.[Embodiment 99] The method of Embodiment 98, wherein the ocular symptoms comprise comeal microsyst-like epithelial keratopathy > Grade 2.[Embodiment 100] The method of any one of Embodiments 1-97, wherein the patient does not have ocular symptoms prior to the administration of the vasoconstrictor.[Embodiment 101] The method of Embodiment 100, wherein the patient is at risk of developing ocular symptoms.[Embodiment 102] The method of any one of Embodiments 1-101, wherein the patient is a human patient.[Embodiment 103.] Use of a vasoconstrictor in the manufacture of a medicament for use in the method of any one of Embodiments 1-102.[Embodiment 104.] Use of an AMC in the manufacture of a medicament for use in the method of any one of Embodiments 1-102.BRIEF DESCRIPTIONS OF THE DRA WINGS

[0038] FIG. 1 shows concentrations of radioactivity in blood and plasma at specified times after a single 30-minute intravenous infusion of M-sulfo-SPDB-3H-DM4 (Group 1, 12 mg / kg) or M-SPDB-3H-DM4 (Group 2, 12 mg / kg) to male Dutch Belted rabbits.

[0039] FIG. 2A shows concentrations of radioactivity in cornea at specified times after a single 30-minute intravenous infusion of M-sulfo-SPDB-3H-DM4 (Group 1, 12 mg / kg) or M- SPDB-3H-DM4 (Group 2, 12 mg / kg) to male Dutch Belted rabbits.

[0040] FIG. 2B shows the ratio of the maximum concentrations (Cmax) and exposure (AUC) of M-SPDB-3H-DM4 to M-sulfo-SPDB-3H-DM4 in various samples obtained from rabbits treated with the AMCs.

[0041] FIG. 3 shows the structure of IMGN853 (mirvetuximab soravtansine; ELAHERE®).

[0042] FIG. 4 shows the structure of IMGN 151.DETAILED DESCRIPTION OF THE DISCLOSUREI. Definitions

[0043] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0044] The term “antibody-drug conjugate” or ADC as used herein refers to a compound or a derivative thereof defined by the generic formula: D-L-A, wherein D = cytotoxic drug, L = linker, and A = antibody or antigen-binding fragment thereof. ADCs can also be defined by the generic formula in reverse order: A-L-C.

[0045] The term “antibody-maytansinoid conjugate” or “AMC” as used herein refers to an ADC wherein the cytotoxic drug is a maytansinoid.

[0046] As used herein, the term “cytotoxic drug” refers to a substance that inhibits or prevents one or more cellular functions and / or causes cell death. In some aspects, the cytotoxic agent is a maytansinoid, e.g., DM1, DM4, or DM21.

[0047] Exemplary AMCs comprising DM1 or DM4 are disclosed in PCT publication WO 2011 / 106528, which is herein incorporated by reference in its entirety.

[0048] Exemplary AMCs comprising DM21 are disclosed in PCT publications WO 2018 / 160539 and WO 2020 / 223221, each of which is herein incorporated by reference in its entirety.

[0049] An AMC can comprise the site-specific DM21 linkage of "DM21C" represented by the following structural formula:

[0050] An AMC can also comprise the lysine-linked DM21 "L-DM21," "DM21-L," or "DM21L," which are represented by the following structural formula:wherein Di is shown above, coupled to an antibody by a linker, e.g., a y-maleimidobutyric acid N-succinimidyl ester (GMBS) or a N-(y-maleimidobutryloxy)sulfosuccinimide ester (sulfo-GMBS or sGMBS) linker. The GMBS and sulfo-GMBS (or sGMBS) linkers are known in the art and can be presented by the following structural formula:

[0051] A “linker” is any chemical moiety that is capable of linking a drug, such as maytansinoid, to a cell-binding agent such as an antibody or antigen-binding fragment thereof in a stable, covalent manner. Linkers can be susceptible to or be substantially resistant to cleavage (e.g., acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, or disulfide bond cleavage) at conditions under which the compound or the antibody remains active. Suitable linkers are well known in the art and include, for example, disulfide groups and thioether groups.

[0052] The terms “human folate receptor 1,” “FRa,” “folate receptor alpha (FR-a),” or “FOLR1” as used herein, refers to any native human FRa polypeptide, unless otherwise indicated. The term “FRa” encompasses “full-length,” unprocessed FRa polypeptide as well as any form of FRa polypeptide that results from processing within the cell. The term also encompasses naturally occurring variants of FRa, e.g., those encoded by splice variants and allelic variants. The FRa polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. Where specifically indicated, “FRa” can be used to refer to a nucleic acid that encodes a FRa polypeptide. Human FRa sequences are known and include, for example, the sequences publicly available at UniProtKB Accession No. P15328 (including isoforms).

[0053] The term “anti-FRa antibody,” “FRa antibody,” or “an antibody that binds to FRa” refers to an antibody that is capable of binding FRa with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting FRa. As used herein, such antibodies include, for example, monospecific (e.g., bivalent monospecific) antibodies. As used herein, such antibodies also include, for example, bispecific (e.g., biparatopic) antibodies. Unless otherwise specified, the extent of binding of an anti-FRa antibody to an unrelated, non-FRa protein is less than about 10% of the binding of the antibody to FRa asmeasured, e.g., by a radioimmunoassay (RIA). Non-limiting examples of FRa antibodies are known in the art and are disclosed in PCT publications WO 2011 / 106528 and WO 2020 / 223221, each of which is herein incorporated by reference in its entirety. The sequences of exemplary anti-FRa antibodies and antigen-binding fragments thereof are provided in Tables 1-8.

[0054] The term “IMGN853” (also known as “mirvetuximab soravtansine” or ELAHERE®) refers to the AMC described herein containing the huMovl9 (or M9346A) antibody, the sulfoSPDB linker, and the DM4 maytansinoid. The “huMovl9” (or “M9346A”) antibody is an anti-FRa antibody comprising the full length heavy chain of SEQ ID NO: 35 (comprising the variable heavy chain sequence SEQ ID NO:27, which is underlined in the context of SEQ ID NO:35 in Table 8 below) and the full length light chain of SEQ ID NO:33 (comprising the variable light chain sequence SEQ ID NO:24, which is underlined in the context of SEQ ID NO:33 in Table 7 below). The structure of IMGN853 is shown in Figure 3.

[0055] The huMovl9 (M9346A) antibody is encoded by the plasmids deposited with the American Type Culture Collection (ATCC), located at 10801 University Boulevard, Manassas, VA 20110 on April 7, 2010 under the terms of the Budapest Treaty and having ATCC deposit nos. PTA-10772 and PTA-10773 or 10774. DM4 refers to N2’ -deacetyl -N2’-(4-mercapto-4- methyl-1 -oxopentyl) maytansinoid. “SulfoSPDB” refers to the N-succinimidyl 4-(2- pyridyldithio)-2-sulfobutanoate) linker.

[0056] The term “IMGN151” refers to the AMC described herein containing a biparatopic antibody the B5327A antibody and the DM21-L-GMBS (i.e., DM21-L-G) linker payload. The B5327A antibody is an asymmetric biparatopic anti-FRa antibody comprising the amino acid sequences of SEQ ID NOs: 30-32. The structure of IMGN151 is shown in Figure 4.

[0057] The terms “Disintegrin and Metalloproteinase Domain-containing Protein 9” and “ADAM9” as used herein, refers to any native human ADAM9 polypeptide, unless otherwise indicated. The term “ADAM9” encompasses “full-length,” unprocessed ADAM9 polypeptide as well as any form of ADAM9 polypeptide that results from processing within the cell. The term also encompasses naturally occurring variants of ADAM9, e.g., those encoded by splice variants and allelic variants. The ADAM9 polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. Human ADAM9 sequences are known and include, for example, the sequences publicly available at (NCBI Sequence NP_003807, including a 28 amino acid residue signal sequence, shown underlined) (including isoforms). .

[0058] The term “anti-ADAM9 antibody,” “ADAM9 antibody,” or “an antibody that binds to ADAM9” refers to an antibody that is capable of binding ADAM9 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting ADAM9. Unless otherwise specified, the extent of binding of an anti-ADAM9 antibody to an unrelated, non- ADAM9 protein is less than about 10% of the binding of the antibody to FRa as measured, e.g., by a radioimmunoassay (RIA). Non-limiting examples of ADAM9 antibodies are known in the art and are disclosed in PCT publications WO 2018 / 119196 and WO 2020 / 005945, each of which is herein incorporated by reference in its entirety. The sequences of exemplary anti-ADAM9 antibodies and antigen-binding fragments thereof are provided in Tables 1-4, 7, and 8.

[0059] The term “IMGC936” refers to the AMC described herein containing the MGA021 antibody and the DM21C linker-payload. The “MGA021” antibody is an anti-ADAM9 antibody comprising the full length heavy chain of SEQ ID NO:36 (comprising the variable heavy chain sequence SEQ ID NO:28, which is underlined in the context of SEQ ID NO:36 in Table 8 below) and the full length light chain of SEQ ID NO:34 (comprising the variable light chain sequence SEQ ID NO:25, which is underlined in the context of SEQ ID NO:34 in Table 7 below).

[0060] The terms “elevated,” “increased expression,” or “overexpression” when referring to the amount of a polypeptide or nucleic acid (e.g., ADAM9 or FRa) in a particular tumor, tissue, or cell sample refers to a polypeptide or a nucleic acid encoding such a polypeptide that is present at a level higher than that which is present in a healthy or nondiseased (native, wild type) tissue or cells of the same type or origin. Such increased expression or overexpression can be caused, for example, by mutation, gene amplification, increased transcription, increased translation, or increased protein stability.

[0061] Protein (e.g., FRa or ADAM9) expression can be measured by immunohistochemistry and given a “staining intensity score” or a “staining uniformity score” by comparison to calibrated controls exhibiting defined scores (e.g., an intensity score of 3 is given to the test sample if the intensity is comparable to the level 3 calibrated control or an intensity of 2 is given to the test sample if the intensity is comparable to the level 2 calibrated control). For example, a score of 1, 2, or 3, or a score of 2, or 3, by immunohistochemistry indicates an increased expression of the protein (e.g., FRa or ADAM9). A staining uniformity that is heterogeneous or homogeneous is also indicative of protein (e.g., FRa or ADAM9) expression. The staining intensity and staining uniformity scores can be used alone or in combination (e.g., 2 homo, 2 hetero, 3 homo, 3 hetero, etc.). Staining uniformity can also beexpressed as percentage (%) of cells staining at a certain intensity (e.g., 25% of cells staining at intensity of 1, 2, or 3; 50% of cells staining at intensity of 1, 2, or 3; 75% of cells staining at intensity of 1, 2, or 3. In another example, an increase in protein (e.g., FRa or ADAM9) expression can be determined by detection of an increase of at least 2-fold, at least 3-fold, or at least 5-fold relative to control values (e.g., expression level in a tissue or cell from a subject without cancer or with a cancer that does not have elevated values). Exemplary immunohistochemical methods of measuring FRa and ADAM9 are found in PCT Publications WO 2015 / 031815 and WO2022 / 192134, respectively, each of which is herein incorporated by reference in its entirety.

[0062] The term “antibody” means 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 through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term “antibody” encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antibody, and any other modified immunoglobulin molecule so long as the antibodies exhibit the desired biological activity. As used herein, such antibodies include, for example, bispecific (e.g., biparatopic) antibodies. An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g. IgGl, IgG2, IgG3, IgG4, IgAl 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.

[0063] The term “antibody fragment” or “antibody fragment thereof’ refers to a portion of an intact antibody. An “antigen-binding fragment” refers to a portion of an intact antibody that binds to an antigen. An antigen-binding fragment can contain the antigenic determining variable regions of an intact antibody. Examples of antibody fragments include, but are not limited to Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single chain antibodies. Antibody fragments can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.

[0064] A “monoclonal” antibody or antigen-binding fragment thereof refers to a homogeneous antibody or antigen-binding fragment population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against differentantigenic determinants. The term “monoclonal” antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, “monoclonal” antibody or antigen-binding fragment thereof refers to such antibodies and antigen-binding fragments thereof made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0065] The term “humanized” antibody or antigen-binding fragment thereof refers to forms of non-human (e.g. murine) antibodies or antigen-binding fragments that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from the complementarity determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g. mouse, rat, rabbit, hamster) that have the desired specificity, affinity, and capability (“CDR grafted”) (Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239: 1534-1536 (1988)). In some instances, the Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody or fragment from a non-human species that has the desired specificity, affinity, and capability. The humanized antibody or antigen-binding fragment thereof can be further modified by the substitution of additional residues either in the Fv framework region and / or within the replaced non-human residues to refine and optimize antibody or antigen-binding fragment thereof specificity, affinity, and / or capability. In general, the humanized antibody or antigen-binding fragment thereof 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 or antigen-binding fragment thereof can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Pat. 5,225,539; Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-973 (1994), and Roguska et al., Protein Eng. 9(10):895-904 (1996). In some aspects, a “humanized antibody” is a resurfaced antibody.

[0066] A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination.The variable regions of the heavy and light chain each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies. There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability (i.e., Kabat et al., Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda Md.), “Kabat”); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al, J. Molec. Biol. 273:927-948 (1997)). In addition, combinations of these two approaches are sometimes used in the art to determine CDRs.

[0067] A “constant” region of an antibody is not involved directly in binding an antibody to an antigen, but exhibits various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity

[0068] The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed., 1991, National Institutes of Health, Bethesda, Md.) (“Kabat”).

[0069] The amino acid position numbering as in Kabat, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al. (Sequences of Immunological Interest. 5th Ed., 1991, National Institutes of Health, Bethesda, Md.), (“Kabat”). Using this numbering system, the actual linear amino acid sequence can contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or CDR of the variable domain. For example, a heavy chain variable domain can include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, etc. according to Kabat) after heavy chain FR residue 82. The Kabat numbering of residues can be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence. Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). TheAbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software.

[0070] The term “human” antibody or antigen-binding fragment thereof means an antibody or antigen-binding fragment thereof produced by a human or an antibody or antigen-binding fragment thereof having an amino acid sequence corresponding to an antibody or antigen-binding fragment thereof produced by a human made using any technique known in the art. This definition of a human antibody or antigen-binding fragment thereof includes intact or full-length antibodies and fragments thereof.

[0071] “Binding affinity” generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure.

[0072] By “specifically binds,” it is generally meant that an antibody binds to an epitope via its antigen binding domain, and that the binding entails some complementarity between the antigen binding domain and the epitope. According to this definition, an antibody is said to “specifically bind” to an epitope when it binds to that epitope, via its antigen binding domain more readily than it would bind to a random, unrelated epitope. The term“specificity” is used herein to qualify the relative affinity by which a certain antibody binds to a certain epitope. For example, antibody “A” may be deemed to have a higher specificity for a given epitope than antibody “B,” or antibody “A” may be said to bind to epitope “C” with a higher specificity than it has for related epitope “D ”

[0073] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer can be linear or branched, it can comprise modified amino acids, and it can be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. It is understood that, because the polypeptides of this disclosure are based upon antibodies, in certain aspects, the polypeptides can occur as single chains or associated chains.

[0074] “Bispecific antibodies“ refer to antibodies that bind to two different epitopes. The epitopes can be on the same target antigen or can be on different target antigens.

[0075] “Biparatopic antibodies” are bispecific antibodies that bind to two different nonoverlapping epitopes on the same target antigen (e.g., FRa).

[0076] In some aspects, the FRa antibodies or antigen binding fragments thereof disclosed herein are multivalent molecules. The term “valent” as used within the current application denotes the presence of a specified number of binding sites in an antibody molecule. A natural antibody for example or a full length antibody according to the invention has two binding sites and is “bivalent.” The term “tetravalent,” denotes the presence of four binding sites in an antigen binding protein. The term “trivalent” denotes the presence of three binding sites in an antibody molecule. The term “bispecific, tetravalent,” as used herein denotes an antigen binding protein according to the invention that has four antigen-binding sites of which at least one binds to a first antigen and at least one binds to a second antigen or another epitope of the antigen.

[0077] “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the application includes instances where the circumstance occurs and instances where it does not. For example, the phrase “optionally substituted” means that a nonhydrogen substituent may or may not be present on a given atom, and, thus,the application includes structures wherein a non-hydrogen substituent is present and structures wherein a nonhydrogen substituent is not present.

[0078] 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, and leukemia. More particular examples of such cancers include fallopian tube cancer, squamous cell cancer, lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung), gastroesophageal 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 cancers. The cancer can be a cancerthat expresses FRa (“FRa-expressing cancer”). The cancer can be a cancer that expresses ADAM9 (“ADAM9-expressing cancer”).

[0079] The terms “cancer cell,” “tumor cell,” and grammatical equivalents refer to the total population of cells derived from a tumor or a pre-cancerous lesion, including both non- tumorigenic cells, which comprise the bulk of the tumor cell population, and tumorigenic stem cells (cancer stem cells). As used herein, the term “tumor cell” will be modified by the term “non-tumorigenic” when referring solely to those tumor cells lacking the capacity to renew and differentiate to distinguish those tumor cells from cancer stem cells.

[0080] An “advanced” cancer is one which has spread outside the site or organ of origin, either by local invasion or metastasis. The term “advanced” cancer includes both locally advanced and metastatic disease.

[0081] “Metastatic” cancer refers to cancer that has spread from one part of the body ) to another part of the body.

[0082] A “refractory” cancer is one that progresses even though an anti -tumor treatment, such as a chemotherapy, is administered to the cancer patient.

[0083] A “recurrent” cancer is one that has regrown, either at the initial site or at a distant site, after a response to initial therapy.

[0084] A “relapsed” patient is one who has signs or symptoms of cancer after remission. Optionally, the patient has relapsed after adjuvant or neoadjuvant therapy.

[0085] The term “maintenance therapy” refers to therapy that is given to help keep cancer from coming back after it has disappeared following the initial therapy.

[0086] The term subject refers to any animal (c.g.. a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.

[0087] The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. The formulation can be sterile.

[0088] An “effective amount” of an antibody, , or other drug as disclosed herein is an amount sufficient to carry out a specifically stated purpose.

[0089] t he term therapeutically effective amount refers to an amount of an antibody,, or other drug effective to “treat” a disease or disorder in a subject or mammal.

[0090] Terms such as “treating” or “treating” or “to treat” or “alleviating” or “to alleviate” refer to therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder. Thus, those in need of treatment include those already diagnosed with or suspected of having the disorder. In certain aspects, a subject is successfully “treated” for cancer according to the methods of the present disclosure if the patient shows one or more of the following: a reduction in the number of or complete absence of cancer cells; a reduction in the tumor size; inhibition of or an absence of cancer cell infiltration into peripheral organs including, for example, the spread of cancer into soft tissue and bone; inhibition of or an absence of tumor metastasis; inhibition or an absence of tumor growth; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; reduction in tumorigenicity, tumorigenic frequency, or tumorigenic capacity, of a tumor; reduction in the number or frequency of cancer stem cells in a tumor; differentiation of tumorigenic cells to a non- tumorigenic state; increased progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), a reduced time to progression (TTP), or any combination thereof. In certain aspects, a subject is successfully “treated” for corneal adverse events according to the methods of the present disclosure if the patient is cured of, shows relief of, has reduced symptoms of, and / or shows no progression of one or more comeal conditions or disorders associated with the administration of an antibody maytansinoid conjugate (e.g., IMGN853), including, but not limited to punctate keratitis (superficial keratitis, superficial punctate keratitis, punctate epithelial erosion), nonconfluent keratitis,confluent keratitis, keratopathy (microcystic epithelial change, non-staining punctate epithelial keratopathy, subepithelial inclusion cyst), nonconfluent keratopathy, confluent keratopathy, cornea epithelial defect, corneal ulcer, cornea stromal opacity, comeal perforation, or any combination thereof. In certain aspects, a subject is successfully “treated” for comeal adverse events according to the methods of the present disclosure if the patient is administered the treatment that has been shown to decrease the incidence rate and / or severity of one or more comeal conditions or disorders associated with the administration of an antibody maytansinoid conjugate (e.g., IMGN853), including, but not limited to punctate keratitis (superficial keratitis, superficial punctate keratitis, punctate epithelial erosion), nonconfluent keratitis, confluent keratitis, keratopathy (microcystic epithelial change, nonstaining punctate epithelial keratopathy, subepithelial inclusion cyst), nonconfluent keratopathy, confluent keratopathy, cornea epithelial defect, comeal ulcer, cornea stromal opacity, comeal perforation, or any combination thereof. In certain aspects, a subject is successfully “treated” for comeal adverse events according to the methods of the present disclosure if the patient is administered the treatment that has been shown to decrease the incidence rate and / or severity of one or more comeal conditions or disorders associated with the administration of an antibody maytansinoid conjugate compared to that observed in patients receiving the same dose and dosing regimen of the antibody maytansinoid conjugate (e.g., IMGN853), but receiving prophylactic steroid eye drops instead of receiving treatment with the vasoconstrictor. In certain aspects, a subject is successfully “treated” for comeal adverse events according to the methods of the present disclosure if the patient is administered the treatment that has been shown to decrease the incidence rate and / or severity of one or more comeal conditions or disorders associated with the administration of an antibody maytansinoid conjugate compared to that observed in patients receiving the same dose and dosing regimen of the antibody maytansinoid conjugate (e.g., IMGN853), but receiving a 1% prednisolone acetate ophthalmic suspension 6 times daily on days 1-4 and 4 times daily on days 5 to 8 after the administration of the antibody maytansinoid conjugate, instead of receiving treatment with the vasoconstrictor (e.g., brimonidine tartrate ophthalmic solution). In certain aspects, a subject is successfully “treated” for cancer according to the methods of the present disclosure if the patient is administered a treatment comprising an antibody maytansinoid conjugate (e.g., IMGN853) and a vasoconstrictor, wherein the patient experiences a decreased incidence rate and / or severity of one or more comeal conditions or disorders associated with the administration of the antibody maytansinoid conjugate compared to that observed in patients receiving the same dose and dosing regimen of theantibody maytansinoid conjugate without a vasoconstrictor. In certain aspects, a subject is successfully “treated” for corneal adverse events according to the methods of the present disclosure if the likelihood the patient will suffer from, will have worse symptoms of and / or will show progression of one or more comeal conditions or disorders associated with the administration of an antibody maytansinoid conjugate (e.g., IMGN853), including, but not limited to punctate keratitis (superficial keratitis, superficial punctate keratitis, punctate epithelial erosion), nonconfluent keratitis, confluent keratitis, keratopathy (microcystic epithelial change, non-staining punctate epithelial keratopathy, subepithelial inclusion cyst), nonconfluent keratopathy, confluent keratopathy, cornea epithelial defect, comeal ulcer, cornea stromal opacity (clinically significant), comeal perforation, or any combination thereof is reduced. In certain aspects, the comeal condition or disorder associated with the administration of an antibody maytansinoid conjugate (e.g., IMGN853) is a > Grade 2 comeal condition or disorder. In certain aspects, the comeal condition or disorder associated with the administration of an antibody maytansinoid conjugate (e.g., IMGN853) is a > Grade 3 comeal condition or disorder. In certain aspects, the comeal condition or disorder associated with the administration of an antibody maytansinoid conjugate (e.g., IMGN853) is a > Grade 4 comeal condition or disorder. In certain aspects, the comeal condition or disorder associated with the administration of an antibody maytansinoid conjugate (e.g., IMGN853) does not comprise cornea stromal opacity. In certain aspects, the comeal condition or disorder associated with the administration of an antibody maytansinoid conjugate (e.g., IMGN853) does not comprise cornea subepithelial opacity. In certain aspects, a subject is successfully “treated” for ocular adverse events according to the methods of the present disclosure if the patient is cured of, shows relief of, has reduced symptoms of, and / or shows no progression of one or more ocular symptoms associated with the administration of an antibody maytansinoid conjugate (e.g., IMGN853), including, but not limited to blurred vision, dry eyes, eye pain, floaters and photophobia.

[0091] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to methods that may be used to enable delivery of the AMC to the desired site of biological action. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In one aspect, the AMC is administered intravenously.

[0092] Unless specifically stated or obvious from context, as used herein, the term “about” is as used herein, includes the recited number ± 10%. Thus, “about 10” means 9 to 11. As is understood by one skilled in the art, reference to “about” a value or parameter herein includes (and describes) instances that are directed to that value or parameter per se. For example, a description referring to “about X” includes a description of “X.”

[0093] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an aspect for a variable or aspect herein includes that aspect as any single aspect or in combination with any other aspects or portions thereof.

[0094] As used in the present disclosure and claims, the singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise.

[0095] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. In this disclosure, "comprises," "comprising," "containing" and "having" and the like can mean "includes," "including," and the like;"consisting essentially of' or "consists essentially" are open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art aspects.

[0096] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both “A and B,” “A or B,” “A,” and “B.” Uikewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0097] Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.II. Ocular Toxicity

[0098] Ocular toxicity has been associated with AMCs containing antibodies that bind to a variety of targets, including e.g., FRa, ADAM9, CD19, and CanAg. Therefore, the ocular toxicity is believed to be independent of the antibody target. As described herein, ocular toxicity can be reduced by administering a vasoconstrictor to a patient after the AMC isadministered to the patient. As demonstrated here, AMCs can accumulate in ocular tissue, particularly in the epithelium of the cornea and the concentration of AMCs in the cornea epithelium can peak after the concentration of the AMCs peaks in the blood / plasma. Moreover, the concentration of AMCs can remain higher in the cornea epithelium as the concentration of the AMC decreases in the blood / plasma. Accordingly, administration of the vasoconstrictor after the administration of the AMC (as opposed to only prior to the administration of the AMC or only at the same time as administration of the AMC) may ensure that the vasoconstrictor is present at sufficient quantities to decrease exposure of the ocular tissues to the AMC.

[0099] Accordingly, as provided herein administration of the vasoconstrictor and AMC can reduce an ocular toxicity associated with the AMC. In some aspects, administration of the vasoconstrictor and AMC reduces Grade >2 ocular toxicity associated with the AMC. In some aspects, administration of the vasoconstrictor and AMC reduces Grade >3 ocular toxicity associated with the AMC. In some aspects, the ocular toxicity is dry eye, blurred vision, comeal keratopathy, comeal microcysts, comeal edema, and / or comeal haze. In some aspects, the ocular toxicity is comeal keratopathy. In some aspects, the ocular toxicity is comeal microcysts. In some aspects, the ocular toxicity is a comeal condition or disorder. In some aspects, the ocular toxicity is a > Grade 2 comeal condition or disorder. In some aspects, the ocular toxicity is a > Grade 3 comeal condition or disorder. In some aspects, the ocular toxicity is punctate keratitis, for example, superficial keratitis, superficial punctate keratitis, or punctate epithelial erosion. In some aspects, the ocular toxicity is nonconfluent keratitis. In some aspects, the ocular toxicity is confluent keratitis. In some aspects, the ocular toxicity is keratopathy, for example, microcystic epithelial change, non-staining punctate epithelial keratopathy, or subepithelial inclusion cyst. In some aspects, the ocular toxicity is nonconfluent keratopathy. In some aspects, the ocular toxicity is confluent keratopathy. In some aspects, the ocular toxicity is cornea epithelial defect. In some aspects, the ocular toxicity is comeal ulcer. In some aspects, the ocular toxicity is cornea stromal opacity. In some aspects, the ocular toxicity is comeal perforation. In certain aspects, the ocular toxicity does not comprise cornea stromal opacity. In certain aspects, the ocular toxicity does not comprise cornea subepithelial opacity.

[0100] As provided herein, “reducing” ocular toxicity can refer to a measure that cures, slows down, lessen symptoms of, delays, and / or halts progression of ocular toxicity.III. Vasoconstrictors

[0101] As provided herein, a vasoconstrictor can be used to reduce ocular toxicity associated with an antibody maytansinoid conjugate (AMC). A vasoconstrictor is an agent that causes narrowing of the walls of blood vessels. In some aspects, a vasoconstrictor is an alpha- 2 adrenergic receptor agonist.

[0102] Exemplary vasoconstrictors include, but are not limited to brimonidine, apraclonidine, dipivefrin, epinephrine, naphazoline, phenylephrine, oxymetazoline, tetryzoline, and combinations thereof. In some aspects, the vasoconstrictor is brimonidine, e.g., brimonidine tartrate.

[0103] A vasoconstrictor can be administered to a patient, according to the methods provided herein, in an ophthalmic solution, i.e., as eye drops. The ophthalmic solution can be refrigerated.

[0104] A vasoconstrictor can be administered to a patient, according to the methods provided herein, at a particular concentration. In some aspects, the vasoconstrictor is administered, e.g., in an ophthalmic solution, at a concentration of 0.1% to 0.5%. In some aspects, the vasoconstrictor is administered, e.g., in an ophthalmic solution, at a concentration of 0.1% to 0.4%. In some aspects, the vasoconstrictor is administered, e.g., in an ophthalmic solution, at a concentration of 0.1% to 0.3%. In some aspects, the vasoconstrictor is administered, e.g., in an ophthalmic solution, at a concentration of 0.1% to 0.25%. In some aspects, the vasoconstrictor is administered, e.g., in an ophthalmic solution, at a concentration of 0.1% to 0.2%. In some aspects, the vasoconstrictor is administered, e.g., in an ophthalmic solution, at a concentration of about 0.1%, about 0.15%, or about 0.2%.

[0105] In some aspects provided herein, a vasoconstrictor (e.g., brimonidine) is administered to a patient after an AMC is administered to the patient. For example, a vasoconstrictor (e.g., brimonidine) can be administered on at least 2 days after administration of the AMC, at least 3 days after administration of the AMC, at least 4 days after administration of the AMC, at least 5 days after administration of the AMC, at least 6 days after the administration of the AMC, at least 7 days after the administration of the AMC, at least 8 days after the administration of the AMC, at least 9 days after the administration of the AMC, at least 10 days after the administration of the AMC, at least 14 days after the administration of the AMC, at least 21 days after the administration of the AMC, or at least 28 days after the administration of the AMC. The at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days can be consecutivedays. The at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days can be non-consecutive days. For example, the vasoconstrictor can be administered on at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days after the administration of the AMC, wherein the vasoconstrictor is administered every other day after administration of the AMC. The vasoconstrictor can be also administered on at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days after the administration of the AMC, wherein the vasoconstrictor is administered once every three days, after the administration of the AMC. The vasoconstrictor can be also administered on at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days after the administration of the AMC, wherein the vasoconstrictor is administered once every three days, after the administration of the AMC.

[0106] In some aspects, the AMC (e.g., IMGN853) is administered on day 1 of a treatment cycle, and the vasoconstrictor is administered at least once on day 1 after the administration of the AMC. In some aspects, the AMC (e.g., IMGN853) is administered on day 1 of a treatment cycle, and the vasoconstrictor is administered on day 1 before the administration of the AMC and at least once after the administration of the AMC. In some aspects, the AMC (e.g., IMGN853) is administered on day 1 of a treatment cycle, and the vasoconstrictor is administered on day 1 once before the administration of the AMC and twice after the administration of the AMC. In some aspects, the administration of the vasoconstrictor before the administration of the AMC on day 1 of the treatment cycle is no more than 60 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, or 2 minutes before the administration of the AMC. In some aspects, the first administration of the vasoconstrictor after the administration of the AMC on day 1 of the treatment cycle is no more than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours after the administration of the AMC. In some aspects, the vasoconstrictor is further administered on days 2-14, days 2-13, days 2-12, days 2-11, days 2- 10, days 2-9, days 2-8, days 2-7, days 2-6, days 2-5, days 2-4, days 2-3, or day 2 of the treatment cycle. In some aspects, the vasoconstrictor is further administered three times a day on days 2- 14, days 2-13, days 2-12, days 2-11, days 2-10, days 2-9, days 2-8, days 2-7, days 2-6, days 2- 5, days 2-4, days 2-3, or day 2 of the treatment cycle. In some aspects, the vasoconstrictor is further administered on days 2-8 of the treatment cycle. In some aspects, the vasoconstrictor is further administered three times a day on days 2-8 of the treatment cycle. In some aspects, the vasoconstrictor is further administered on days 2-7 of the treatment cycle. In some aspects, thevasoconstrictor is further administered three times a day on days 2-7 of the treatment cycle. In some aspects, the vasoconstrictor is further administered on days 2-6 of the treatment cycle. In some aspects, the vasoconstrictor is further administered three times a day on days 2-6 of the treatment cycle. In some aspects, the vasoconstrictor is further administered on days 2-9 of the treatment cycle. In some aspects, the vasoconstrictor is further administered three times a day on days 2-9 of the treatment cycle. In some aspects, the treatment cycle is a 21 day treatment cycle. In some aspects, the treatment cycle is a 28 day treatment cycle.

[0107] In some aspects provided herein, a vasoconstrictor (e.g., brimonidine) is administered to a patient receiving an AMC in a cycle. The cycle can be, for example, a three- week cycle (Q3W). Accordingly, in some aspects, an AMC is administered once every three weeks, and a vasoconstrictor (e.g., brimonidine) is administered at least once a day (e.g., optionally two, three, or four times a day) throughout the three weeks. In some aspects, an AMC is administered once every three weeks, and a vasoconstrictor (e.g., brimonidine) is administered at least once a day (e.g., optionally two, three, or four times a day) for the first week of the cycle, but not administered for the remaining two weeks of the cycle. In some aspects, an AMC is administered once every three weeks, and a vasoconstrictor (e.g., brimonidine) is administered at least once a day (e.g., optionally two, three, or four times a day) for the first two weeks of the cycle, but not administered for the remaining week of the cycle.

[0108] In some aspects, a patient received an AMC in a four-week cycle (Q4W). Accordingly, in some aspects, an AMC is administered once every four weeks and a vasoconstrictor (e.g., brimonidine) is administered at least once a day (e.g., optionally two, three, or four times a day) throughout the four weeks. In some aspects, an AMC is administered once every four weeks, and the vasoconstrictor (e.g., brimonidine) is administered at least once a day (e.g., optionally two, three, or four times a day) for the first week of the cycle, but not administered for the remaining three weeks of the cycle. In some aspects, an AMC is administered once every four weeks, and the vasoconstrictor (e.g., brimonidine) is administered at least once a day (e.g., optionally two, three, or four times a day) for the first two weeks of the cycle, but not administered for the remaining two weeks of the cycle. In some aspects, an AMC is administered once every four weeks, and a vasoconstrictor (e.g., brimonidine) is administered at least once a day (e.g., optionally two, three, or four times a day) for the first three weeks of the cycle, but not administered for the remaining week of the cycle.

[0109] As provided herein, a vasoconstrictor (e.g., brimonidine) can be administered to a patient after an AMC is administered. However, in addition to being administered afteradministration of an AMC, a vasoconstrictor (e.g., brimonidine) can also be administered prior to the administration of the AMC and / or at the same time as administration of the AMC. Accordingly, in some aspects, a vasoconstrictor (e.g., brimonidine) is administered on the day prior to administration of the AMC and / or prior to the AMC administration on the same day as the AMC administration (e.g., immediately prior to administration of the AMC or within one hour, two hours, or three hours prior to the administration of the AMC), as well as after administration of the AMC (e.g., on at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days after the administration of the AMC).

[0110] In some aspects provided herein, a vasoconstrictor (e.g., brimonidine) can be administered once on each day that it is administered after administration of the AMC. For example, in some aspects, a vasoconstrictor (e.g., brimonidine) is administered once daily on at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days after the administration of the AMC.[oni] In some aspects provided herein, a vasoconstrictor (e.g., brimonidine) can be administered multiple times on each day that it is administered. For example, in some aspects, a vasoconstrictor (e.g., brimonidine) is administered about 2 to about 10 times per day on at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days after the administration of the AMC. In some aspects, a vasoconstrictor (e.g., brimonidine) is administered twice per day on at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days after the administration of the AMC. In some aspects, a vasoconstrictor (e.g., brimonidine) is administered three times per day on at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days after the administration of the AMC. In some aspects, a vasoconstrictor (e.g., brimonidine) is administered four times per day on at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, or at least 28 days after the administration of the AMC.

[0112] In some aspects provided herein, a vasoconstrictor (e.g., brimonidine) can be administered at a varying number of times of day. For example, in some aspects, a vasoconstrictor (e.g., brimonidine) can be administered two or three times per day for about one week or about two weeks and then once per day for about one week or about two weeks.IV. Antibody Maytansinoid Conjugates (AMCs)

[0113] Provided herein are methods of reducing ocular toxicity associated with AMCs. AMCs comprise a maytansinoid linked to an antibody or antigen-binding fragment thereof via a linker.

[0114] In some aspects, an AMC comprises 1-10 maytansinoids per antibody or antigenbinding fragment thereof. In some aspects, an AMC comprises 1-5 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 1 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 2 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 3 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 4 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 5 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 6 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 7 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 8 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 9 maytansinoids per antibody or antigen-binding fragment thereof. In some aspects, an AMC comprises 10 maytansinoids per antibody or antigen-binding fragment thereof.A. Maytansinoids

[0115] Examples of suitable maytansinoids that can be included in AMCs include esters of maytansinol and maytansinol analogs. Exemplary maytansinoids have been described previously in WO 2011 / 106528, WO 2018 / 160539, and WO 2020 / 223221, each of which is herein incorporated by reference in its entirety.

[0116] In some aspects, an AMC comprises N2-deacetyl - / V2-(3-mercapto- 1-oxopropyl)- maytansine (DM1), N2-deacetyl- / V-2(4-mercapto-l-oxopentyl)-maytansine (termed DM3), or N2-deacetyl -N2-(4-mercapto-4-methyl- 1 -oxopentyl) maytansine (DM4), or DM21, each of which was previously described in PCT Application Publication Nos. WO 2011 / 10652 and WO 2020 / 223221, each of which is herein incorporated by reference in its entirety.

[0117] In some aspects, an AMC comprises a maytansinoid compound represented by the following formula:L2' — A — NH— CR1R2-S-L1— D (jj) or a pharmaceutically acceptable salt thereof, wherein:L2 is represented by the following structural formulas:wherein:Rx, Ry, Rxand Ry, for each occurrence, are independently H, -OH, halogen, - O-(Ci-4 alkyl), -SO3H, -NR4oR4iR42+, or a C1-4 alkyl optionally substituted with -OH, halogen, -SO3H or NR4oR4iR42+, wherein R40, R41 and R42 are each independently H or a Ci -4 alkyl;1 and k are each independently an integer from 1 to 10;JCB is -C(=O)OH or -COE, wherein -COE is a reactive ester;A is an amino acid or a peptide comprising 2 to 20 amino acids;R1and R2are each independently H or a Ci-3alkyl;Li is represented by the following formula:-CR3R4-(CH2)I-8-C(=O)-; wherein R3and R4are each independently H or Me, and the -C(=O)- moiety in Li is connected to D;D is represented by the following formula:and q is an integer from 1 to 20. In some aspects q is an integer from 1 to 10. In some aspects q is an integer from 2 to 5. In some aspects, q is an integer from 3 to 4.

[0118] In some aspects, the maytansinoid of the present invention is represented by the following formula:or a pharmaceutically acceptable salt thereof, wherein:A’ is an amino acid or a peptide comprising 2 to 20 amino acids (z.e., A-NH2);R1and R2are each independently H or a Ci-3alkyl;Li is -CR3R4-(CH2)I-8-C(=O)-; R3and R4are each independently H or Me;D is represented by the following formula:; and q is an integer from 1 to 20. In some aspects q is an integer from 1 to 10. In some aspects q is an integer from 2 to 5. In some aspects, q is an integer from 3 to 4.

[0119] In some aspects, the maytansinoid of the present invention is represented by the following formula:or a pharmaceutically acceptable salt thereof, wherein:Rxand Ry, for each occurrence, are independently H, -OH, halogen, -O-(Ci-4 alkyl), - SO3H, -NR4oR4iR42+, or a C1-4 alkyl optionally substituted with -OH, halogen, SO3H orNR4oR4iR42+, wherein R40, R41 and R42 are each independently H or a C1-4 alkyl; k is an integer from 1 to 10A is an amino acid residue or a peptide comprising 2 to 20 amino acid residues;R1and R2are each independently H or a Ci-3alkyl;Li is -CR3R4-(CH2)I-8-C(=O)-; R3and R4are each independently H or Me;D is represented by the following formula:; and q is an integer from 1 to 20. In some aspects q is an integer from 1 to 10. In some aspects q is an integer from 2 to 5. In some aspects, q is an integer from 3 to 4.

[0120] In a specific aspect, the maytansinoid compound is represented by the following formula:

[0121] wherein D 1 is represented by the following formula:

[0122] Additional examples of suitable maytansinol esters include those having a modified aromatic ring and those having modifications at other positions. Such suitable maytansinoids are disclosed in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; 4,362,663; 4,364,866; 4,450,254; 4,322,348; 4,371,533; 5,208,020; 5,416,064; 5,475,092; 5,585,499; 5,846,545; 6,333,410; 7,276,497 and 7,473,796, each of which is herein incorporated by reference in its entirety. In addition, several descriptions for producing such antibody-maytansinoid conjugates are provided in U.S. Patent Nos. 6,333,410, 6,441,163, 6,716,821, and 7,368,565, each of which is herein incorporated by reference in its entirety.B. Linkers

[0123] Any suitable linkers known in the art can be used in the AMCs of the present disclosure. In certain aspects, the linkers are bifunctional linkers. As used herein, the term “bifunctional linker” refers to modifying agents that possess two reactive groups; one of which is capable of reacting with a cell binding agent while the other one reacts with the maytansinoid compound to link the two moieties together. Such bifunctional crosslinkers are well known in the art (see, for example, Isalm and Dent in Bioconjugation chapter 5, p218- 363, Groves Dictionaries Inc. New York, 1999). For example, bifunctional crosslinking agents that enable linkage via a thioether bond include A'-succinimidyl-4-(N- maleimidomethylj-cyclohexane- 1 -carboxylate (SMCC) to introduce maleimido groups, or with A'-succinim idyl -4-(iodoacctyl)-aminobcnzoatc (SIAB) to introduce iodoacetyl groups.Other bifunctional crosslinking agents that introduce maleimido groups or haloacetyl groups on to a cell binding agent are well known in the art (see US Patent Publication Nos. 2008 / 0050310, 20050169933, available from Pierce Biotechnology Inc. P.O. Box 117, Rockland, IL 61105, USA) and include, but not limited to, bis-maleimidopolyethyleneglycol (BMPEO), BM(PEO)2, BM(PEO)3, N-(P-maleimidopropyloxy)succinimide ester (BMPS), y-maleimidobutyric acid N-succinimidyl ester (GMBS), s-maleimidocaproic acid N-hydroxy succinimide ester (EMCS), 5 -maleimido valeric acid NHS, HBVS, N-succinimidyl -4-(N-maleimidomethyl)-cyclohexane- 1 -carboxy-(6-amidocaproate), which is a “long chain” analog of SMCC (LC-SMCC), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4-(4-N-maleimidophenyl)-butyric acid hydrazide or HC1 salt (MPBH), N- succinimidyl 3-(bromoacetamido)propionate (SBAP), N-succinimidyl iodoacetate (SIA), K- maleimidoundecanoic acid N-succinimidyl ester (KMUA), N-succinimidyl 4-(p- maleimidophenyl)-butyrate (SMPB), succinimidyl-6-(P-maleimidopropionamido)hexanoate (SMPH), succinimidyl-(4-vinylsulfonyl)benzoate (SVSB), dithiobis-maleimidoethane (DTME), 1,4-bis-maleimidobutane (BMB), l,4-bismaleimidyl-2,3-dihydroxybutane (BMDB), bis-maleimidohexane (BMH), bis-maleimidoethane (BMOE), sulfosuccinimidyl 4- (N-maleimido-methyl)cyclohexane- 1-carboxylate (sulfo-SMCC), sulfosuccinimidyl(4-iodo- acetyl)aminobenzoate (sulfo-SIAB), m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (sulfo-MBS), N-(y-maleimidobutryloxy)sulfosuccinimide ester (sulfo-GMBS or sGMBS), N- (s-maleimidocaproyloxy)sulfosuccimido ester (sulfo-EMCS), N-(K- maleimidoundecanoyloxy)sulfosuccinimide ester (sulfo-KMUS), and sulfosuccinimidyl 4-(p- maleimidophenyl)butyrate (sulfo- SMPB) .

[0124] Heterobifunctional crosslinking agents are bifunctional crosslinking agents having two different reactive groups. Heterobifunctional crosslinking agents containing both an amine -reactive N-hydroxy succinimide group (NHS group) and a carbonyl-reactive hydrazine group can also be used to link the cytotoxic compounds described herein with a cell-binding agent (e.g., antibody). Examples of such commercially available heterobifunctional crosslinking agents include succinimidyl 6-hydrazinonicotinamide acetone hydrazone (SANH), succinimidyl 4-hydrazidoterephthalate hydrochloride (SHIH) and succinimidyl hydrazinium nicotinate hydrochloride (SHNH). Conjugates bearing an acid- labile linkage can also be prepared using a hydrazine -bearing benzodiazepine derivative of the present disclosure. Examples of bifunctional crosslinking agents that can be used include succinimidyl -p-formyl benzoate (SFB) and succinimidyl -p-formylphenoxyacetate (SFPA).

[0125] Bifunctional crosslinking agents that enable the linkage of cell binding agent with cytotoxic compounds via disulfide bonds are known in the art and include / V-succinimidyl-3-(2-pyridyldithio)propionate (SPDP). A'-succinimidyl-4-(2- pyridyldithio)pentanoate (SPP), A'-siiccinimidyl-4-(2-pyridyldithio)butanoatc (SPDB), / V-succinimidyl-4-(2-pyridyldithio)2-sulfo butanoate (sulfo-SPDB or sSPDB) to introduce dithiopyridyl groups. Other bifunctional crosslinking agents that can be used to introduce disulfide groups are known in the art and are disclosed in U.S. Patents 6,913,748, 6,716,821 and US Patent Publications 2009 / 0274713 and 2010 / 0129314, each of which is herein incorporated by reference in its entirety. Alternatively, crosslinking agents such as 2-iminothiolane, homocysteine thiolactone or S-acetylsuccinic anhydride that introduce thiol groups can also be used.

[0126] In some aspects, an AMC for use in the methods provided herein comprises an antibody or antigen-binding fragment thereof linked to a maytansinoid through the s-amino group of a lysine residue of the antibody or antigen-binding fragment thereof.

[0127] In some aspects, an AMC for use in the methods provided herein an antibody or antigen-binding fragment thereof is linked to the maytansinoid through a Cys thiol group.C. Antibodies and Antigen-Binding Fragments Thereof

[0128] Examples of suitable antibodies and antigen-binding fragments thereof that can be included in AMCs are provided herein. The antibodies or antigen-binding fragments thereof can be e.g., monoclonal antibodies or antigen-binding fragments thereof. In some aspects, an antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof. In some aspects, an antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof.

[0129] In some aspects, an antibody or antigen-binding fragment thereof comprises one or more polypeptides comprising one or more of the CDR sequences described herein. For example, an antibody or antigen-binding fragment thereof can comprise one or more of the light chain CDR sequences (i.e., EC CDR1, LC CDR2, and LC CDR3) and / or one or more of the heavy chain CDR sequences (i.e., HC CDR1, HC CDR2, and HC CDR3) shown below in Tables 1 and 2.

[0130] An antibody or antigen-binding domain can comprise a variable heavy chain (VH) and a variable light chain (VL). The VH and the VL can be separate polypeptides or can parts of the same polypeptide (e.g., in an scFv).Exemplary FRa antibodies and antigen binding fragments thereof

[0131] In some aspects, the antibody or antigen-binding fragment thereof binds to FRa. FRa antibodies and antigen binding fragments thereof are known in the art and have been disclosed, for example, in PCT Application Publication Nos. WO 2011 / 106528 Al; WO 2012 / 135675 A3; WO 2012 / 138749 Al; WO 2014 / 036495 A3; and WO 2015 / 031815 A2; each of which is herein incorporated by reference in its entirety. Additional FRa antibodies have been disclosed in US Patent Nos. 8,557,966 B2; 8,709,432 B2; 9,702,881 B2; and 9,637,547 B2; and U.S. Patent Application Publication No. US-2012-0282282 Al, each of which is herein incorporated by reference in its entirety. In addition, the FRa antibody huMovl9 (M9346A) is encoded by the plasmids deposited with the American Type Culture Collection (ATCC), located at 10801 University Boulevard, Manassas, VA 20110 on April 7, 2010 under the terms of the Budapest Treaty and having ATCC deposit nos. PTA-10772 and PTA-10774. As provided herein, an FRa-binding domain can be the FRa-binding domain (e.g., the six CDRs or the VH and VE) of any of these antibodies or antigen-binding fragments thereof.

[0132] By way of example, an FRa-antibody or antigen-binding fragment thereof can comprise the CDR sequences of the huMovl9 antibody, and / or the FR57 antibody. The CDR sequences of the huMovl9 and FR57 antibodies are provided in Tables 1 and 2.

[0133] In some aspects, an FRa-antibody or antigen-binding fragment thereof comprises (a) VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 1-3, respectively; and (b) VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 7-9, respectively. In some aspects, an FRa-antibody or antigenbinding fragment thereof comprises (a) VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 1-3, respectively; and (b) VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 9, respectively. In some aspects, an FRa-antibody or antigen-binding fragment thereof comprises (a) VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 4-6, respectively and (b) VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 10-12, respectively. In some aspects, an FRa-antibody or antigenbinding fragment thereof comprises (a) VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 4-6, respectively and (b) VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 15, 16, and 12, respectively.

[0134] In some aspects, an FRa-antibody or antigen-binding fragment thereof is a biparatopic antibody and comprises (a) VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 1-3, respectively; and VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 7-9, respectively and (b) VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 4-6, respectively and VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 10-12, respectively. In some aspects, an FRa-antibody or antigen-binding fragment thereof is a biparatopic antibody and comprises (a) VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 1-3, respectively; and VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 9, respectively and (b) VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 4-6, respectively and VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 15, 16, and 12, respectively.

[0135] In some aspects, an FRa-antibody or antigen-binding fragment thereof comprises the light and / or heavy chain variable sequences of the huMovl9 antibody and / or the FR57 antibody. The light chain variable sequences and heavy chain variable sequences of huMovl9 and FR57 are provided in Tables 3 and 4 below. In some aspects, an FRa-antibody or antigenbinding fragment thereof comprises the light and / or heavy chain variable sequences of SEQ ID NOs: 24 and 27, respectively. In some aspects, an FRa-antibody or antigen-binding fragment thereof comprises the light and / or heavy chain variable sequences of SEQ ID NOs: 23 and 26, respectively.

[0136] In some aspects, an FRa-antibody or antigen-binding fragment thereof comprises an scFv. The scFv can comprise the light and / or heavy chain variable sequences of the huMovl9 antibody or the FR57 antibody. The sequence of an exemplary scFv comprising the light and heavy chain variable sequences of the FR57 antibody is provided in Table 5 below.

[0137] In some aspects, an FRa-antibody or antigen-binding domain comprises a VL having 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 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity to SEQ ID NO:23, optionally wherein the VL comprises VL CDR1, VL CDR2, and VL CDR3 sequences of SEQ ID NOs: 1-3, respectively. In some aspects, an FRa-antibody or antigen-binding domain a VL having 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 96%, at least about 97%, at least about 98%, at least about 99%, or 100%sequence identity to SEQ ID NO:24, optionally wherein the VL comprises VL CDR1, VL CDR2, and VL CDR3 sequences of SEQ ID NOs: 4-6, respectively.

[0138] In some aspects, an FRa-antibody or antigen-binding domain comprises a VH having 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 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity to SEQ ID NO:26, optionally wherein the VH comprises VH CDR1, VH CDR2, and VH CDR3 sequences of SEQ ID NOs: 7-9, respectively or SEQ ID NOs: 13, 14, and 9, respectively. In some aspects, an FRa-antibody or antigenbinding domain comprises a VH having 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 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity to SEQ ID NO:27, optionally wherein the VH comprises VH CDR1, VH CDR2, and VH CDR3 sequences of SEQ ID NOs: 10-12, respectively or SEQ ID NOs: 15, 16, and 12, respectively.

[0139] In some aspects, an FRa-antibody or antigen-binding domain comprises a VL and a VH. The VL and the VH can be separate polypeptides. The VL and the VH can also be parts of the same polypeptide, e.g., a polypeptide comprising a VL, a linker, and a VH. A polypeptide comprising a VL, a linker, and a VH can be in the orientation VL-linker-VH or the orientation VH-linker-VL.

[0140] Accordingly, in some aspects, an FRa-antibody or antigen-binding domain (e.g., scFv) comprises, from N- to C-terminus: a VL comprising the amino acid sequence of SEQ ID NO:23, a linker (e.g., a glycine-serine linker), and a VH comprising the amino acid sequence of SEQ ID NO:26. In some aspects, an FRa-antibody or antigen-binding domain comprises, from N to C terminus: a VH comprising the amino acid sequence of SEQ ID NO:23, a linker (e.g., a glycine-serine linker), and a VL comprising the amino acid sequence of SEQ ID NO:26.

[0141] In some aspects, an FRa-antibody or antigen-binding domain (e.g., scFv) comprises, from N- to C-terminus: a VL comprising the amino acid sequence of SEQ ID NO:24, a linker (e.g., a glycine-serine linker), and a VH comprising the amino acid sequence of SEQ ID NO:27. In some aspects, an FRa-binding domain comprises, from N to C terminus: a VH comprising the amino acid sequence of SEQ ID NO:27, a linker (e.g., a glycine-serine linker), and a VL comprising the amino acid sequence of SEQ ID NO:24.

[0142] Linkers that can be used to connect a VH and a VL are known in the art. For example, a linker can be a glycine-serine linker. In some aspects, the linker can be of any length and can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, or 60 or more amino acids. In other aspects, alinker useful for the present disclosure has at least one amino acid and less than 100 amino acids, less than 90 amino acids, less than 80 amino acids, less than 70 amino acids, less than 60 amino acids, less than 50 amino acids, less than 40 amino acids, less than 30 amino acids, less than 20 amino acids, less than 19 amino acids, less than 18 amino acids, less than 17 amino acids, less than 16 amino acids, less than 15 amino acids, less than 14 amino acids, less than 13 amino acids, or less than 12 amino acids. In one aspect, the linker sequence comprises glycine amino acid residues. In other instances, the linker sequence comprises a combination of glycine and serine amino acid residues.

[0143] In some aspects, an FRa-antibody or antigen-binding domain comprises a linker fused in frame between the VH and the VL. In some aspects, such glycine / serine linkers comprises any combination of the amino acid residues, including, but not limited to, the peptide GGGS (SEQ ID NO:39) or GGGGS (SEQ ID NO:40) or repeats of the same, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more repeats of these given peptides. The glycine / serine linkers disclosed herein comprises an amino acid sequence of (GS)n, (GGS)n, (GGGS)n, (GGGGS)n, or (GGGGS)n, wherein n is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one aspect, the linker sequence is GGGGSGGGGSGGGGS (SEQ ID NO:41) (also noted as (Gly4Ser)3). In another aspect, the linker sequence is GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:42) (also noted as (Gly4Ser)4).

[0144] In some aspects, an FRa-antibody or antigen-binding domain (e.g., scFv) comprises the amino acid sequence of SEQ ID NO:29.

[0145] In some aspects, an FRa-antibody or antigen-binding fragment thereof comprises a scFv comprising an amino acid sequence 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 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity to SEQ ID NO:29, optionally wherein the scFv comprises VL CDR1, VL CDR2, and VL CDR3 sequences of SEQ ID NOs: l-3, respectively and VH CDR1, VH CDR2, and VH CDR3 sequences of SEQ ID NOs: 7-9, respectively or SEQ ID NOs: 13, 14, and 9, respectively. In some aspects, an FRa-antibody or antigen-binding domain comprises a scFv comprising the amino acid sequence of SEQ ID NO:29.

[0146] In some aspects, an FRa-antibody or antigen-binding domain comprises a VL comprising the amino acid sequence of SEQ ID NO:23 and a VH comprising the amino acid sequence of SEQ ID NO:26. In some aspects, an FRa-antibody or antigen-binding domain comprises a VL comprising the amino acid sequence of SEQ ID NO:24 and a VH comprising the amino acid sequence of SEQ ID NO:27.

[0147] In some aspects, a biparatopic FRa-antibody or antigen-binding domain comprises (i) a VL comprising the amino acid sequence of SEQ ID NO:23 and a VH comprising the amino acid sequence of SEQ ID NO:26 and (ii) a VL comprising the amino acid sequence of SEQ ID NO:24 and a VH comprising the amino acid sequence of SEQ ID NO:27. In some aspects, a biparatopic FRa-antibody or antigen-binding domain comprises (i) a VL comprising the amino acid sequence of SEQ ID NO:23 and a VH comprising the amino acid sequence of SEQ ID NO:26 on separate polypeptide chains and (ii) an scFv comprising (a) a VL comprising the amino acid sequence of SEQ ID NO:24 and (b) a VH comprising the amino acid sequence of SEQ ID NO:27. In some aspects, a biparatopic FRa-antibody or antigen-binding domain comprises (i) an scFv comprising (a) a VL comprising the amino acid sequence of SEQ ID NO:23 and (b) a VH comprising the amino acid sequence of SEQ ID NO:26 and (ii) a VL comprising the amino acid sequence of SEQ ID NO:24 and a VH comprising the amino acid sequence of SEQ ID NO:27 on separate polypeptide chains.

[0148] In some aspects, a biparatopic FRa-antibody or antigen-binding domain comprises (i) an scFv comprising the amino acid sequence of SEQ ID NO:29 and (ii) a VL comprising the amino acid sequence of SEQ ID NO:24 and a VH comprising the amino acid sequence of SEQ ID NO:27 on separate polypeptide chains.

[0149] In certain aspects, an FRa-antibody or antigen-binding fragment thereof binds to the same epitope of FRa as an antibody comprising the amino acid sequences of SEQ ID NO:23 and SEQ ID NO: 26.

[0150] In certain aspects, an FRa-antibody or antigen-binding fragment thereof binds to the same epitope of FRa as an antibody comprising the amino acid sequences of SEQ ID NO:24 and SEQ ID NO: 27.

[0151] In certain aspects, an FRa-antibody or antigen-binding fragment thereof, e.g., a biparatopic antibody or antigen-binding fragment thereof (i) binds to the same epitope of FRa as an antibody comprising the amino acid sequences of SEQ ID NO:23 and SEQ ID NO:26 and (ii) binds to the same epitope of FRa as an antibody comprising the amino acid sequences of SEQ ID NO:24 and SEQ ID NO:27.

[0152] In certain aspects, an FRa-antibody or antigen-binding fragment thereof binds to human FRa but not FOLR2 or FOLR3.

[0153] In certain aspects, an FRa-antibody or antigen-binding fragment thereof is a monospecific FRa-antibody or antigen-binding fragment thereof. In certain aspects, an FRa- antibody or antigen-binding fragment thereof is a monospecific bivalent FRa-antibody or antigen-binding fragment thereof.

[0154] In certain aspects, an FRa-antibody or antigen-binding fragment thereof is a biparatopic FRa-antibody or antigen-binding fragment thereof. The biparatopic anti-FRa antibodies or antigen binding fragments thereof can comprise a combination of FRa-binding domains that bind to non-overlapping epitopes of FRa.

[0155] In some aspects, a biparatopic anti-FRa antibody or antigen binding fragment thereof is bivalent. A bivalent biparatopic anti-FRa antibody or antigen binding fragment thereof can comprise, for example, two FRa-binding domains comprising scFvs, two FRa- binding domains comprising VHs and VLs on separate polypeptide chains, or one FRa-binding domain comprising an scFv and one FRa-binding domain that comprises a VH and a VL on separate polypeptide chains.

[0156] In some aspects, a bivalent biparatopic anti-FRa antibody or antigen binding fragment thereof comprises a single FRa-binding domain that is an scFv and a single FRa- binding domain that comprises a VH and a VL on separate polypeptides. In such aspects, the scFv can be fused to a heavy chain constant region and the VH can be fused to a heavy chain constant region. In some aspects, the constant regions have “knob and hole” sequences. The “knob” sequence can be in the heavy chain constant region fused to the scFv, and the “hole” sequence can be fused to the constant region fused to the VH. Alternatively the “hole” mutation can be in the heavy chain constant region fused to the scFv, and the “knob” sequence can be fused to the constant region fused to the VH. Sequences of an exemplary biparatopic FRa antibody of such formats are found in Table 6.

[0157] In one aspect, a FRa biparatopic antibody or antigen binding fragment thereof comprises a T366W mutation in the "knobs chain" and T366S, L368A, Y407V mutations in the "hole chain," and optionally an additional interchain disulfide bridge between the CH3 domains by, e.g., introducing a Y349C mutation into the "knobs chain" and a E356C mutation or a S354C mutation into the “hole chain;” R409D, K370E mutations in the "knobs chain" and D399K, E357K mutations in the "hole chain;” a T366W mutation in the "knobs chain" and T366S, L368A, Y407V mutations in the "hole chain;" R409D, K370E mutations in the "knobs chain" and D399K, E357K mutations in the "hole chain;" Y349C, T366W mutations in one of the chains and E356C, T366S, L368A, Y407V mutations in the counterpart chain; and Y349C, T366W mutations in one chain and S354C, T366S, L368A, Y407V mutations in the counterpart chain (numbering according to the EU numbering system).

[0158] In one aspect, a biparatopic anti-FRa antibody or antigen-binding fragment thereof comprises the polypeptides of SEQ ID NOs: 30-32.

[0159] In some aspects, a biparatopic anti-FRa antibody or antigen binding fragment thereof is trivalent.

[0160] In some aspects, a biparatopic anti-FRa antibody or antigen-binding fragment thereof is tetravalent. Tetravalent antibodies and are described, for instance, in M.J. Coloma, S.L. Morrison, Nat. Bioiechnol.. 15(2): 159-63 (1997), which is herein incorporated by reference in its entirety.

[0161] The biparatopic antibodies or antigen binding fragments thereof of the present disclosure can further comprise a linker. In some aspects, the linker can link a first antibody or antigen binding fragment thereof to the second antibody or antigen binding fragment thereof from N-terminus to C-terminus. In other aspects, the linker can link the second polypeptide to the first polypeptide from N-terminus to C-terminus.

[0162] In one aspect, the biparatopic antibodies or antigen binding fragments thereof comprises a linker sequence located between the first peptide, antibody or antigen binding fragment thereof and the second peptide, antibody or antigen binding fragment thereof. The linker can be of any length and can comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, or 60 or more amino acids. In other aspects, a linker useful for the present disclosure has at least one amino acid and less than 100 amino acids, less than 90 amino acids, less than 80 amino acids, less than 70 amino acids, less than 60 amino acids, less than 50 amino acids, less than 40 amino acids, less than 30 amino acids, less than 20 amino acids, less than 19 amino acids, less than 18 amino acids, less than 17 amino acids, less than 16 amino acids, less than 15 amino acids, less than 14 amino acids, less than 13 amino acids, or less than 12 amino acids. In one aspect, the linker sequence comprises glycine amino acid residues. In other instances, the linker sequence comprises a combination of glycine and serine amino acid residues.

[0163] In some aspects, such glycine / serine linkers can comprises any combination of the amino acid residues, including, but not limited to, the peptide GGGS (SEQ ID NO:39) or GGGGS (SEQ ID NO:40) or repeats of the same, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more repeats of these given peptides. The glycine / serine linkers disclosed herein comprises an amino acid sequence of (GS)n, (GGS)n, (GGGS)n, (GGGGS)n, or (GGGGS)n, wherein n is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one aspect, the linker sequence is GGGGSGGGGSGGGGS (SEQ ID NO:41) (also noted as (Gly4Ser)3). In another aspect, the linker sequence is GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:42) (also noted as (Gly4Ser)4).Exemplary ADAM9 antibodies and antigen binding fragments thereof

[0164] In some aspects, the antibody or antigen-binding fragment thereof binds to ADAM9. Exemplary ADAM9 antibodies and antigen-binding fragments thereof have been described in WO 2018 / 119196 and WO 2020 / 005945, each of which is herein incorporated by reference in its entirety.

[0165] By way of example, an ADAM9-antibody or antigen-binding fragment thereof can comprise the CDR sequences of the hMAB-A(2I.2) antibody. The CDR sequences of the hMAB-A(2I.2) antibody are provided in Tables 1 and 2.

[0166] In some aspects, an ADAM9-antibody or antigen-binding fragment thereof comprises (a) VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 17-19, respectively; and (b) VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 20-22, respectively.

[0167] In some aspects, an ADAM9-antibody or antigen-binding fragment thereof comprises the light and / or heavy chain variable sequences of the hMAB-A(2I.2) antibody. The light chain variable sequences and heavy chain variable sequences of hMAB-A(2I.2) are provided in Tables 3 and 4.

[0168] In some aspects, an ADAM9-antibody or antigen-binding domain comprises a VL having 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 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity to SEQ ID NO:25, optionally wherein the VL comprises VL CDR1, VL CDR2, and VL CDR3 sequences of SEQ ID NOs: 17-19, respectively.

[0169] In some aspects, an ADAM9-antibody or antigen-binding domain comprises a VH having 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 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity to SEQ ID NO:28, optionally wherein the VH comprises VH CDR1, VH CDR2, and VH CDR3 sequences of SEQ ID NOs: 20-22, respectively.

[0170] In some aspects, an ADAM9-antibody or antigen-binding fragment thereof comprises the light and / or heavy chain variable sequences of the hMAB-A(2I.2) antibody. The light chain variable sequences and heavy chain variable sequences of hMAB-A(2I.2) are provided in Tables 3 and 4 below. In some aspects, an ADAM9-antibody or antigen-binding fragment thereof comprises the light and / or heavy chain variable sequences of SEQ ID NOs: 25 and 28, respectively.

[0171] In certain aspects, an ADAM9-antibody or antigen-binding fragment thereof is an IgG antibody or antigen-binding fragment thereof. In certain aspects, an ADAM9-antibody or antigen-binding fragment thereof comprises a human IgG constant region.

[0172] In certain aspects, an ADAM9-antibody or antigen-binding fragment thereof is an IgGl antibody or antigen-binding fragment thereof. In certain aspects, an ADAM9-antibody or antigen-binding fragment thereof comprises a human IgGl constant region. In some aspects, the human IgGl constant region comprises the substitutions M252Y, S254T, T256E, and S442C in the CH2-CH3 Domains of the Fc Region.

[0173] In some aspects, an ADAM9-antibody or antigen-binding fragment thereof comprises the light and / or heavy chain sequences of the hMAB-A(2I.2) antibody. The light chain and heavy chain sequences of hMAB-A(2I.2) are provided in Tables 7 and 8 below. In some aspects, an ADAM9-antibody or antigen-binding fragment thereof comprises the light and / or heavy chain sequences of SEQ ID NOs: 34 and 36, respectively.

[0174] In certain aspects, an ADAM9-antibody or antigen-binding fragment thereof binds to the same epitope of ADAM9 as an antibody comprising the amino acid sequences of SEQ ID NO:25 and SEQ ID NO:28.Table 1: Light chain CDR sequences (by Kabat Definition)Table 2: Heavy chain CDR sequencesTable 3. Light Chain Variable SequenceTable 4. Heavy Chain Variable SequenceTable 5. scFv Fusion ProteinsTable 6. Asymmetric-Fc molecules (Knob-in-hole)Table 7. Full Length Light Chain SequencesTable 8. Full Length Heavy Chain SequencesExemplary Antibodies and Antigen-Binding Fragments Thereof

[0175] In some aspects, the antibody or antigen-binding fragment thereof in an AMC that binds to CD37, CanAg, FRa, CD 19, cMET, ADAM9, or HER2.

[0176] In some aspects, an antibody or antigen binding fragment thereof in an AMC comprises a heavy chain constant region, such as an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. In some aspects, the heavy chain constant region is an IgGl heavy chain constant region or an IgG4 heavy chain constant region. Furthermore, in some aspects,an antibody or antigen binding fragment thereof in an AMC can comprise a light chain constant region, either a kappa light chain constant region or a lambda light chain constant region. In some aspects, the light chain constant region is a kappa light chain constant region.

[0177] In some aspects, an antibody or antigen binding fragment thereof in an AMC comprises an altered (e.g., mutated or engineered) Fc region. For example, in some aspects, the Fc region has been altered to reduce or enhance the effector functions of the antibody, alter serum half-life or other functional properties of the antibody. Reduction or elimination of effector function is desirable in certain cases, for example in the case of antibodies whose mechanism of action involves blocking or antagonism, but not killing of the cells bearing a target antigen. Increased effector function is generally desirable when directed to undesirable cells, such as tumor and foreign cells, where the FcyRs are expressed at low levels, for example, tumor-specific B cells with low levels of FcyRIIB (e.g., non-Hodgkin’s lymphoma, CLL, and Burkitt’s lymphoma). As provided herein, AMCs possessing such conferred or altered effector function activity are useful for the treatment and / or prevention of a disease, disorder or infection in which an enhanced efficacy of effector function activity is desired. In some aspects, the Fc region is an isotype selected from IgM, IgA, IgG, IgE, or other isotype.

[0178] Although the Fc Region of the antibody or antigen binding fragment thereof in an AMC may possess the ability to bind to one or more Fc receptors (e.g., FcyR(s)), in certain aspects the antibody or antibody fragment comprises a variant Fc region having an altered binding to FcyRIA (CD64), FcyRIIA (CD32A), FcyRIIB (CD32B), FcyRIIIA (CD 16a) or FcyRIIIB (CD 16b) (relative to the binding exhibited by a wild-type Fc Region), e.g. , will have enhanced binding to an activating receptor and / or will have substantially reduced or no ability to bind to inhibitory receptor(s). Thus, the Fc region of the antibody or antigen binding fragment thereof in an AMC may include some or all of the CH2 domain and / or some or all of the CH3 domain of a complete Fc region, or may comprise a variant CH2 and / or a variant CH3 sequence (that may include, for example, one or more insertions and / or one or more deletions with respect to the CH2 or CH3 domains of a complete Fc Region). Such Fc regions may comprise non-Fc polypeptide portions, or may comprise portions of non-naturally complete Fc regions, or may comprise non-naturally occurring orientations of CH2 and / or CH3 domains (such as, for example, two CH2 domains or two CH3 domains, or in the N-terminal to C- terminal direction, a CH3 domain linked to a CH2 domain, etc.).

[0179] Fc Region modifications identified as altering effector function are known in the art, including modifications that increase binding to activating receptors (e.g., FcyRIIA (CD16A) and reduce binding to inhibitory receptors (e.g, FcyRIIB (CD32B) (see, e.g.,Stavenhagen, et al., Cancer Res. 57(18):8882-8890 (2007)). Table 9 lists exemplary single, double, triple, quadruple and quintuple substitutions (numbering is that of the EU index as in Kabat, and substitutions are relative to the amino acid sequence of SEQ ID NO:43) of exemplary modification that increase binding to activating receptors and / or reduce binding to inhibitory receptors.Table 9. Variations of Exemplary Activating Fc Regions

[0180] Exemplary variants of human IgGl Fc Regions with reduced binding to CD32B and / or increased binding to CD16A contain F243L, R292P, Y300L, V305I, or P396L substitutions, wherein the numbering is that of the EU index as in Kabat. These amino acid substitutions may be present in a human IgGl Fc Region in any combination. In one aspect, the variant human IgGl Fc Region contains a F243L, R292P and Y300L substitution. In another aspect, the variant human IgGl Fc Region contains a F243L, R292P, Y300L, V305I and P396L substitution.

[0181] In some aspects, the antibody or antigen binding fragment thereof in an AMC comprises an immunoglobulin heavy chain constant region containing a modification that decreases effector function (see, e.g., Idusogie et al., J. Immunol. 166:2571-2575 (2001); Sazinsky etal., PNAS USA 105:20167-20172 (2008); Davis etal., J. Rheumatol. 34:2204-2210 (2007); Bolt et al., Eur. J. Immunol. 23:403-411 (1993); Alegre et al., Transplantation 57: 1537-1543 (1994); Xu et al., Cell Immunol. 200: 16-26 (2000); Cole et al., Transplantation 68:563-571 (1999); Hutchins et al., PNAS USA 92: 11980-11984 (1995); Reddy et al., J. Immunol. 164: 1925-1933 (2000); WO97 / 11971, and W007 / 106585; U.S. Appl. Publ. 2007 / 0148167A1; McEarchem et al., Blood 109: 1185-1192 (2007); Strohl, Curr. Op. Biotechnol. 20:685-691 (2009); and Kumagai etal., J. Clin. Pharmacol. 47: 1489-1497 (2007), the contents of each of which is herein incorporated by reference in its entirety).

[0182] In some aspects, the Fc region of the antibody or antigen binding fragment thereof in an AMC exhibits decreased (or substantially no) binding to an effector receptor selected from the group consisting of: FcyRIA (CD64), FcyRIIA (CD32A)(allotypes R131 and H131), FcyRIIB (CD32B), FcyRIIIA (CD16a) (allotype V158 and F158) and FcyRIIIB (CD16b)(allotype Fcylllb-NAl and FcyIIIb-NA2); relative to the binding exhibited by the wild-type IgG Fc Region (SEQ ID NO:43). In some aspects, the antibody or antigen-binding fragment Fc region variant effector receptor binding affinity has been reduced to 1 / 10 or less, 1 / 50 or less, or 1 / 100 or less as, compared to the binding affinity of the corresponding antibody or antibody binding fragment comprising the wildtype Fc region of the corresponding immunoglobulin .

[0183] In a specific aspect, the antibody or antigen-binding fragment in the AMC comprises an IgG Fc region that exhibits reduced effector function (e.g., reduced ADCC) and comprise a modification at one or more amino acid positions selected from the group consisting of 233, 234, 235, 236, 237, 238, 239, 265, 266, 267, 269, 270, 271, 295, 296, 297, 298, 300, 324, 325, 327, 328, 329, 331, and 332, wherein the amino acid position numbering is according to the EU index as set forth in Kabat. In one aspect, the CH2-CH3 domain of the antibody or antigen-binding fragment in the AMC includes any 1, 2, 3, or 4 of the substitutions: L234A, L235A, D265A, N297Q, N297A, and N297G, wherein the numbering is that of the EU index as in Kabat. In another aspect, the CH2-CH3 domains contain an N297Q substitution, an N297A substitution, or L234A and L235A substitutions, as these mutations abolish FcR binding. Alternatively, the antibody or antigen-binding fragment in the AMC comprises a CH2- CH3 domain of a naturally occurring Fc region that inherently exhibits decreased (or substantially no) binding to FcyRIIIA (CD 16a) and / or reduced effector function (relative to the binding and effector function exhibited by the wild-type IgGl Fc region (SEQ ID NO:43). In a specific aspect, the Fc constant region of the antibody or antigen-binding fragment in the AMC comprises an IgG2 Fc region (SEQ ID NO:44) or an IgG4 Fc region (SEQ ID NO:45). Since the N297A, N297G, N297Q, L234A, L235A and D265A substitutions abolish effector function, in circumstances in which effector function is desired, these substitutions would generally not be employed.

[0184] An IgGl sequence for the CH2 and CH3 Domains of the Fc region-containing antibody or antigen-binding fragment that has reduced or abolished effector function comprises the substitutions L234A / L235A (shown underlined) (SEQ ID NO:46):APEAAGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPAPIEKTISKAK GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG

[0185] An IgGl sequence for the CH2 and CH3 Domains of the Fc region-containing antibody or antigen-binding fragment that has reduced or abolished effector function comprises the substitution N297A (shown underlined) (SEQ ID NO:47):APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYASTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG

[0186] An IgGl sequence for the CH2 and CH3 Domains of the Fc region-containing antibody or antigen-binding fragment that has reduced or abolished effector function comprises the substitution N297Q (shown underlined) (SEQ ID NO:48):APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYQSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG

[0187] In some aspects, the antibody or antigen-binding fragment in the AMC comprises an Fc (immunoglobulin) sequence selected from SEQ ID NO:46, SEQ ID NO:47, or SEQ ID NO:48. In some aspects, antibody or antigen-binding fragment in the AMC comprises an Fc (immunoglobulin) sequence with reduced or abolished effector function (e.g., comprising the substitutions shown above in SEQ ID NO:46, SEQ ID NO:47, and / or SEQ ID NO:48) and comprises one or more knob-in-hole_mutations as disclosed herein. In some aspects, the Fc sequence comprises a knob mutation as disclosed herein. In some aspects, the Fc sequence comprises a hole mutation as disclosed herein.

[0188] In some aspects, the antibody or antigen-binding fragment in the AMC comprises one or more modifications corresponding to: IgGl-C220S, C226S, C229S, P238S; IgGl- C226S, C229S; IgGl-C226S, C229S, E233P, L234V, L235A; IgGl-L234A, L235A; IgGl- L234F, L235E, P331S; IgGl-L234F, L235E, P331S; IgGl-H268Q, A330S, P331S; IgGl- G236R, L328R; IgGl-L235G, G236R, IgGl-N297A; IgGl-N325A, L328R; IgGl-N325L, L328R; IgGl-K326W, E333S; IgG2-V234A, G237A; IgG2-E333S; IgG2 H268Q, V309L, A330S, A331S; IgG4-S228P, L236E; IgG4-F234A, L235A; IgG4-F234A, G237A, E318A; IgG4-L235A, G237A, E318A; IgG4-L236E; IgG2-EU sequence 118-260; and IgG4-EU sequence 261-447; wherein the position numbering is according to the EU index as in Kabat.

[0189] In some aspects, the antibody or antigen-binding fragment in the AMC comprises a heavy chain immunoglobulin constant domain that has reduced CDC activity. In some aspects, the antibody or antigen-binding fragment in the AMC comprises an IgGl heavy chain constant region containing a mutation that decreases CDC activity (see, e.g., WO 1997 / 11971 and WO 2007 / 106585; U.S. Appl. Publ. 2007 / 0148167A1; McEarchem et al., Blood 109: 1185-1192 (2007); Hayden-Ledbetter et al., Clin. Cancer 15:2739-2746 (2009); Lazar et al., PNAS USA 103:4005-4010 (2006); Bruckheimer et al., Neoplasia 11:509-517 (2009); Strohl, Curr. Op. Biotechnol. 20:685-691 (2009); and Sazinsky et al., PNAS USA 105:20167-20172 (2008); each of which is herein incorporated by reference in its entirety). Examples of heavy chain constant domain sequence modifications that decrease CDC include one or more modifications corresponding to: IgGl-C226S, C229S, E233P, L234V, L235A; IgGl-C226S, P230S; IgGl-L234F, L235E, P331S; IgGl-S239D, A330L, I332E; IgG2 EU sequence 118-260; IgG4- EU sequence 261-447; and IgG2-H268Q, V309L, A330S, A331S, according to the EU index

[0190] In some aspects, the antibody or antigen-binding fragment in the AMC comprises a heavy chain immunoglobulin constant domain that contains one or more half-life extending amino acid modifications (e.g., substitutions). Numerous mutations capable of increasing the half-life of an Fc region-containing molecule are known in the art and can be encompassed as components of an antibody or antigen-binding fragment in an AMC. See, e.g., U.S. Patent Nos. 6,277,375; 7,083,784; 7,217,797, and 8,088,376; U.S. Publ. Nos. 2002 / 0147311; and 2007 / 0148164; and PCT Publication Nos. WO 1998 / 23289; WO 2009 / 058492; and WO 2010 / 033279, the contents of each of which is herein incorporated by reference in its entirety.

[0191] The serum half-life of proteins comprising Fc regions may be increased by increasing the binding affinity of the Fc Region for FcRn. The term “half-life” as used herein means a pharmacokinetic property of a molecule that is a measure of the mean survival time of the molecules following their administration. Half-life can be expressed as the time required to eliminate fifty percent (50%) of a known quantity of the molecule from a subject’s (e.g., a human patient or other mammal) body or a specific compartment thereof, for example, as measured in serum, i.e., circulating half-life, or in other tissues. In general, an increase in halflife results in an increase in mean residence time (MRT) in circulation for the administered molecule.

[0192] In some aspects, the antibody or antigen-binding fragment in the AMC comprises a half-life extending amino acid substitution at one or more positions selected from the group consisting of: 238, 250, 252, 254, 256, 257, 256, 265, 272, 286, 288, 303, 305, 307, 308, 309, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, 428, 433, 434, 435, and 436,wherein the amino acid position numbering is according to the EU index. In some aspects, the antibody or antigen-binding fragment in the AMC contains one or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428- 436, wherein the amino acid position numbering is according to the EU index. In some aspects, the antibody or antigen-binding fragment in the AMC contains one or more of a substitution of the amino acid at Kabat position 252 with Tyr, Phe, Trp, or Thr; a substitution of the amino acid at Kabat position 254 with Thr; a substitution of the amino acid at Kabat position 256 with Ser, Arg, Gin, Glu, Asp, or Thr; a substitution of the amino acid at Kabat position 257 with Leu; a substitution of the amino acid at Kabat position 309 with Pro; a substitution of the amino acid at Kabat position 311 with Ser; a substitution of the amino acid at Kabat position 428 with Thr, Leu, Phe, or Ser; a substitution of the amino acid at Kabat position 433 with Arg, Ser, Iso, Pro, or Gin; or a substitution of the amino acid at Kabat position 434 with Trp, Met, Ser, His, Phe, or Tyr. More specifically, the antibody or antigen-binding fragment in the AMC can contain amino acid substitutions relative to a wild-type human IgG constant domain including a substitution of the amino acid at Kabat position 252 with Tyr, a substitution of the amino acid at Kabat position 254 with Thr, and a substitution of the amino acid at Kabat position 256 with Glu.

[0193] In some aspects, the antibody or antigen-binding fragment in the AMC comprises a least one substitution selected from: T250Q, M252Y, S254T, T256E, K288D, T307Q, V308P, A378V, M428L, N434A, N434S, N434H, N434Y, H435K, and Y436I, wherein the numbering is that of the EU index as in Kabat. In further aspects, the antibody or antigen-binding fragment in the AMC comprises substitutions selected from: (a) M252Y, S254T and T256E; (b) M252Y and S254T; (c) M252Y and T256E; (d) T250Q and M428L; (e) T307Q and N434A; (f) A378V and N434A; (g) N434A and Y436I; (h) V308P and N434A; and (i) K288D and H435K.

[0194] In one aspect, the antibody or antigen-binding fragment in the AMC contains a variant IgG Fc Region comprising any 1, 2, or 3 of the substitutions: M252Y, S254T and T256E. In some aspects, the antibody or antigen-binding fragment in the AMC possesses variant Fc regions comprising: (a) one or more mutations which alter effector function and / or FcyR; and (b) one or more mutations which extend serum half-life.Table 10: Immunoglobulin SequencesD. Compositions Comprising AMCs

[0195] As provided herein, AMCs can be provided and / or administered in a composition (e.g., pharmaceutical composition) that contains an average number of maytansinoids per antibody or antigen-binding fragment thereof.

[0196] In certain aspects, for compositions (e.g., pharmaceutical compositions) comprising AMCs, the average number of the maytansinoids agent per antibody or antigen-binding fragment thereof (z. e. , average value of q), also known as Drug -Antibody Ratio (DAR) in the composition is in the range of 1.0 to 8.0. In some aspects, DAR is in the range of 1.0 to 5.0, 1.0 to 4.0, 1.5 to 4.0, 2.0 to 4.0, 2.5 to 4.0, 1.0 to 3.4, 1.0 to 3.0, 3.0 to 4.0, 3.1 to 3.5, 3.1 to 3.7, 3.4 to 3.6, 1.5 to 2.5, 2.0 to 2.5, 1.7 to 2.3, or 1.8 to 2.2. In some aspects, the DAR is less than 4.0, less than 3.8, less than 3.6, less than 3.5, less than 3.0 or less than 2.5. In some aspects, the DAR is in the range of 3.1 to 3.7. In some aspects, the DAR is in the range of 3.1 to 3.4. In some aspects, the DAR is in the range of 3.3 to 3.7. In some aspects, the DAR is in the range of 3.5 to 3.9. In some aspects, the DAR is 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7 or 3.8. In some aspects,the DAR is 3.5. In some aspects, the DAR is in the range of 1.8 to 2.0. In some aspects, the DAR is in the range of 1.7 to 1.9. In some aspects, the DAR is in the range of 1.9 to 2.1. In some aspects, the DAR is 1.9, 2.0 or 2.1.

[0197] In some aspects, for the AMCs of the present invention comprising a biparatopic anti-FRa antibody or an antigen-binding fragment thereof linked to the maytansinoid compound through one or more cysteine thiol group, the DAR is in the range of 1.5 to 2.5, 1.8 to 2.2, 1.1 to 1.9 or 1.9 to 2.1. In some aspects, the DAR is 1.8, 1.9, 2.0 or 2.1E. Exemplary AMCsIMGN853 and related AMCs

[0198] Exemplary AMCs for use in the methods provided herein include IMGN853 and related AMCs. For example, in some aspects, an AMC for use herein comprises a maytansinoid linked (optionally via a sulfo-SPDB linker) to an FRa antibody or antigen-binding fragment thereof comprising the CDRs of SEQ ID NOs:4-6 and 10-12. In some aspects, an AMC for use herein comprises DM4 linked (optionally via a sulfo-SPDB linker) to an FRa antibody or antigen-binding fragment thereof comprising the CDRs of SEQ ID NOs:4-6 and 10-12. In some aspects, a composition comprising such AMC comprises about 3 to about 4 maytansinoids (e.g., DM4) per antibody or antigen-binding fragment thereof. In some aspects, a composition comprising such AMC comprises about 3.4 maytansinoids (e.g., DM4) per antibody or antigenbinding fragment thereof.

[0199] In some aspects, an AMC for use herein comprises a maytansinoid linked (optionally via a sulfo-SPDB linker) to an IgGl FRa antibody comprising the CDRs of SEQ ID NOs:4-6 and 10-12. In some aspects, an AMC for use herein comprises DM4 linked (optionally via a sulfo-SPDB linker) to an IgGl FRa antibody comprising the CDRs of SEQ ID NOs:4-6 and 10-12. In some aspects, a composition comprising such AMC comprises about 3 to about 4 maytansinoids (e.g., DM4) per antibody. In some aspects, a composition comprising such AMC comprises about 3.4 maytansinoids (e.g., DM4) per antibody.

[0200] In some aspects, an AMC for use herein comprises a maytansinoid linked (optionally via a sulfo-SPDB linker) to an FRa antibody or antigen-binding fragment thereof comprising a VL comprising the amino acid sequence of SEQ ID NO:24 and a VH comprising the amino acid sequence of SEQ ID NO:27. In some aspects, an AMC for use herein comprises DM4 linked (optionally via a sulfo-SPDB linker) to an FRa antibody or antigen-binding fragment thereof comprising a VL comprising the amino acid sequence of SEQ ID NO:24 anda VH comprising the amino acid sequence of SEQ ID NO:27. In some aspects, a composition comprising such AMC comprises about 3 to about 4 maytansinoids (e.g., DM4) per antibody or antigen-binding fragment thereof. In some aspects, a composition comprising such AMC comprises about 3.4 maytansinoids (e.g., DM4) per antibody or antigen-binding fragment thereof.

[0201] In some aspects, an AMC for use herein comprises a maytansinoid linked (optionally via a sulfo-SPDB linker) to an IgGl FRa antibody comprising a VL comprising the amino acid sequence of SEQ ID NO:24 and a VH comprising the amino acid sequence of SEQ ID NO:27. In some aspects, an AMC for use herein comprises DM4 linked (optionally via a sulfo-SPDB linker) to an IgGl FRa antibody comprising a VL comprising the amino acid sequence of SEQ ID NO:24 and a VH comprising the amino acid sequence of SEQ ID NO:27. In some aspects, a composition comprising such AMC comprises about 3 to about 4 maytansinoids (e.g., DM4) per antibody. In some aspects, a composition comprising such AMC comprises about 3.4 maytansinoids (e.g., DM4) per antibody.

[0202] In some aspects, an AMC for use herein comprises a maytansinoid linked (optionally via a sulfo-SPDB linker) to an FRa antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO:33 and a heavy chain comprising the amino acid sequence of SEQ ID NO:35. In some aspects, an AMC for use herein comprises DM4 linked (optionally via a sulfo-SPDB linker) to an FRa antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO:33 and a heavy chain comprising the amino acid sequence of SEQ ID NO:35. In some aspects, a composition comprising such AMC comprises about 3 to about 4 maytansinoids (e.g., DM4) per antibody. In some aspects, a composition comprising such AMC comprises about 3.4 maytansinoids (e.g., DM4) per antibody.

[0203] In some aspects, an AMC for use herein is IMGN853.IMGN151 and Related AMCs

[0204] In a first aspect, an AMC for use herein comprises a biparatopic FRa antibody or antigen binding fragment thereof described herein covalently linked to a maytansinoid compound described herein through the s-amino group of one or more lysine residues located on the biparatopic FRa antibody or antigen binding fragment thereof. In one aspect, the is represented by formula (or a pharmaceutically acceptable salt thereof, wherein:CB is a biparatopic anti-FRa antibody or antigen binding fragment thereof;L2 is represented by one of the following formula:wherein:Rx, Ry, Rxand Ry, for each occurrence, are independently H, -OH, halogen, -O-(Ci-4 alkyl), -SO3H, -NR4oR4iR42+, or a C1-4 alkyl optionally substituted with -OH, halogen, SO3H or NR4oR4iR42+, wherein R40, R41 and R42 are each independently H or a C1-4 alkyl;I and k are each independently an integer from 1 to 10;II is an integer from 2 to 5; kl is an integer from 1 to 5; and si indicates the site connected to the cell -binding agent CB and s3 indicates the site connected to the A group;A is an amino acid residue or a peptide comprising 2 to 20 amino acid residues;R1and R2are each independently H or a Ci-3alkyl;Li is represented by the following formula:-CR3R4-(CH2)I-8-C(=O)- wherein R3and R4are each independently H or Me, and the -C(=O)- moiety in Li is connected to D;D is represented by the following formula:; and q is an integer from 1 to 20. In some aspects q is an integer from 1 to 10. In some aspects q is an integer from 2 to 5. In some aspects, q is an integer from 3 to 4.

[0205] In a 1stspecific aspect of the first aspect, an AMC provided herein is represented by formula (I) described above, wherein Rx, Ry, Rxand Ryare all H; and 1 and k are each independently an integer an integer from 2 to 6; and the remaining variables are as described above for formula (I).

[0206] In a 2ndspecific aspect of the first aspect, an AMC provided herein is represented by formula (I) described above, wherein A is a peptide containing 2 to 5 amino acid residues; and the remaining variables are as described above for formula (I) in the first aspect or the 1stspecific aspect. In some aspects, A is a peptide cleavable by a protease. In some aspects, a peptide cleavable by a protease expressed in tumor tissue. In some aspects, A is a peptide having an amino acid that is covalently linked with -NH-CR1R2-S-LI-D selected from the group consisting of Ala, Arg, Asn, Asp, Cit, Cys, selino-Cys, Gin, Glu, Gly, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Vai, each independently as L or D isomer. In some aspects, the amino acid connected to -NH-CR1R2-S-LI-D is an L amino acid.

[0207] In a 3rdspecific aspect of the first aspect, an AMC provided herein is represented by formula (I) described above, wherein A is selected from the group consisting of Gly-Gly- Gly, Ala-Vai, Vai-Ala, D-Val-Ala, Val-Cit, D-Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys,Phe-Cit, Leu-Cit, Ile-Cit, Phe-Ala, Phe-N9-tosyl-Arg, Phe-N9-nitro-Arg, Phe-Phe-Lys, D-Phe- Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Ala-Ala, D-Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala-D-Ala, Ala-Leu-Ala-Leu (SEQ ID NO:49), [3-Ala-Leu-Ala-Leu (SEQ ID NO:50), Gly-Phe-Leu-Gly (SEQ ID N0:51), Val-Arg, Arg-Arg, Val-D-Cit, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val-D-Cit, D-Val-D-Lys, D-Val-D-Arg, D- Arg-D-Arg, Ala-Ala, Ala-D-Ala, D-Ala-Ala, D-Ala-D-Ala, Ala-Met, Gln-Val, Asn-Ala, Gln- Phe, Gin-Ala, D-Ala-Pro, and D-Ala-tBu-Gly, wherein the first amino acid in each peptide is connected to L2 group and the last amino acid in each peptide is connected to -NH-CR1R2-S- Li-D; and the remaining variables are as described for formula (I) in the first aspect or the 1stspecific aspect.

[0208] In a 4thspecific aspect of the first aspect, an AMC provided herein is represented by formula (I) described above, wherein R1and R2are both H; and the remaining variables are as described for formula (I) in the first aspect or the 1st, 2nd, or 3rdspecific aspect.

[0209] In a 5thspecific aspect of the first aspect, an AMC provided herein is represented by formula (I) described above, wherein Li is -(CH2)4-6-C(=O)-; and the remaining variables are as described for formula (I) in the first aspect or the 1st, 2nd, 3rdor 4thspecific aspect.

[0001] In a 6thspecific aspect of the first aspect, an AMC provided herein is represented by formula (I) described above, wherein D is represented by the following formula:and the remaining variables are as described for formula (I) in the first aspect or the 1st, 2nd, 3rd, 4thor 5thspecific aspect.

[0210] In a 7thspecific aspect, an AMC provided herein is represented by the following formula:or a pharmaceutically acceptable salt thereof, wherein:CBA^-N —H is the biparatopic anti-FRa antibody or antigen-binding fragment thereof connected to the L2 group through a Lys amine group;biparatopic anti-FRa antibody or antigen-binding fragment thereof connected to the L2 group through a Cys thiol group;R3and R4are each independently H or Me; ml, m3, nl, rl, si and tl are each independently an integer from 1 to 6; m2, n2, r2, s2 and t2 are each independently an integer from 1 to 7; t3 is an integer from 1 to 12;Di is represented by the following formula:; and q is an integer from 1 to 20. In some aspects q is an integer from 1 to 10. In some aspects q is an integer from 2 to 5. In some aspects, q is an integer from 3 to 4. In a more specific aspect, Di is represented by the following formula:

[0211] In a 8thspecific aspect, an AMC provided herein is represented by the following formula:wherein: ml and m3 are each independently an integer from 2 to 4; m2 is an integer from 2 to 5; rl is an integer from 2 to 6; r2 is an integer from 2 to 5; and the remaining variables are as described in the 7thspecific aspect.

[0212] In a 9thspecific aspect, for the AMCs described in the 7thor 8thspecific aspect, A is Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala, D-Ala-Ala, Vai-Ala, D-Val-Ala, D-Ala-Pro, or D-Ala- tBu-Gly. In a more specific aspect, for the AMCs described in the 7thor 8thspecific aspect, A is L-Ala-D-Ala-L-Ala.

[0213] In a 10thspecific aspect, an AMC provided herein is represented by the following formula:ZLor a pharmaceutically acceptable salt thereof, wherein:A is Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala, D-Ala-Ala, Vai-Ala, D-Val-Ala, D-Ala-Pro, or D-Ala-tBu-Gly, andDi is represented by the following formula:and the remaining variables are as described in the 7th, 8thor 9thspecific aspect. In a more specific aspect, A is L-Ala-D-Ala-L-Ala. In a more specific aspect, Di is represented by the following formula:

[0214] In a 11thspecific aspect, an AMC provided herein is represented by the following formula:wherein Di is represented by the following formula:

[0215] In a more specific aspect, Di is represented by the following formula:

[0216] In a 12thspecific aspect, an AMC provided herein is represented by the following formula:wherein:CBA is a biparatopic anti-FRa antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof comprises (i) light chain complementary determining regions L-CDR1, L-CDR2, and L-CDR3 having the sequences of SEQ ID NOs: 1-3 and heavy chain complementary determining regions H-CDR1, H-CDR2, and H-CDR3 having the sequences of SEQ ID NOs:7-9 and (ii) light chain complementary determining regions L-CDR1, L-CDR2, and L-CDR3 having the sequences of SEQ ID NOs:4-6 and heavy chain complementary determining regions H-CDR1, H-CDR2, and H-CDR3 having the sequences of SEQ ID NOs: 10-12, respectively; q is 1 or 2;Di is represented by the following formula:

[0217] In certain aspects, for the AMC of formula (1-4) or (1-6), the biparatopic anti-FRa antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:23, a VH comprising the amino acid sequence of SEQ ID NO:26, a VL comprising the amino acid sequence of SEQ ID NO:24, and a VH comprising the amino acid sequence of SEQ ID NO:27.

[0218] In a 13thspecific aspect, an AMC provided herein is represented by the following formula:wherein:CBA is a biparatopic anti-FRa antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof comprises (i) light chain complementary determining regions L-CDR1, L-CDR2, and L-CDR3 having the sequences of SEQ ID NOs: 1-3 and heavy chain complementary determining regions H-CDR1, H-CDR2, and H-CDR3 having the sequences of SEQ ID NOs:7-9 and (ii) light chain complementary determining regions L-CDR1, L-CDR2, and L-CDR3 having the sequences of SEQ ID NOs:4-6 and heavy chain complementary determining regions H-CDR1, H-CDR2, and H-CDR3 having the sequences of SEQ ID NOs: 10-12, respectively; q is an integer from 1 to 10, e.g., 1 or 10; and Di is represented by the following formula:

[0219] In certain aspects, for the AMC of formula (1-2), the a biparatopic anti-FRa antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:23, a VH comprising the amino acid sequence of SEQ ID NO:26, a VL comprising the amino acid sequence of SEQ ID NO:24, and a VH comprising the amino acid sequence of SEQ ID NO:27. In certain aspects, for the AMC of formula (1-2), the a biparatopic anti-FRa antibody or antigen-binding fragment thereof comprises polypeptides having the amino acid sequences of SEQ ID NOs: 30, 31, and 32.

[0220] In a 14thaspect, an AMC provided herein comprises a biparatopic anti-FRa antibody coupled to a maytansinoid compound DM21C (also referred to as Mal-LDL-DM or MalC5-LDL-DM) represented by the following structural formula:wherein the biparatopic anti-FRa antibody or antigen binding fragment thereof comprises (i) a light chain variable region and a heavy chain variable region having the sequences of SEQ ID NO:23 and SEQ ID NO:26, respectively, and (ii) a light chain variable region and a heavy chain variable region having the sequences of SEQ ID NO: 14 and SEQ ID NO:27, respectively; and Di is represented by the following formula:

[0221] In one aspect, the AMC is represented by the following structural formula:wherein:CBA is a biparatopic anti-FRa antibody or antigen binding fragment thereof comprises (i) a light chain variable region and a heavy chain variable region having the sequences of SEQ ID NO:23 and SEQ ID NO:26, respectively, and (ii) a light chain variable region and a heavy chain variable region having the sequences of SEQ ID NO:24 and SEQ ID NO:27, respectively; and q is 1 or 2.

[0222] In certain aspects, for compositions (e.g. , pharmaceutical compositions) comprising AMCs of the 14thspecific aspect, DAR is in the range of 1.5 to 2.2, 1.7 to 2.2 or 1.9 to 2. 1. In some aspect, the DAR is 1.7, 1.8, 1.9, 2.0 or 2.1.

[0223] In a 15thspecific aspect, an AMC provided herein comprises a biparatopic anti-FRa antibody or antigen-binding fragment thereof coupled to a maytansinoid compound DM21 (also referred to as DM2 IL, LDL-DM, or compound 14c) represented by the following structural formula:via y-maleimidobutyric acid N-succinimidyl ester (GMBS) or a N- (y-maleimidobutryloxy)sulfosuccinimide ester (sulfo-GMBS or sGMBS) linker. The biparatopic anti-FRa antibody or antigen binding fragment thereof comprises (i) a light chain variable region and a heavy chain variable region having the sequences of SEQ ID NO:23 and SEQ ID NO:26, respectively, and (ii) a light chain variable region and a heavy chain variable region having the sequences of SEQ ID NO:24 and SEQ ID NO:27, respectively.

[0224] The GMBS and sulfo-GMBS (or sGMBS) linkers are known in the art and can be presented by the following structural formula:

[0225] In one aspect, the AMC is represented by the following structural formula:wherein:CBA is a biparatopic anti-FRa antibody or antigen binding fragment thereof comprises (i) a light chain variable region and a heavy chain variable region having the sequences of SEQ ID NO:23 and SEQ ID NO:26, respectively, and (ii) a light chain variable region and a heavy chain variable region having the sequences of SEQ ID NO:24 and SEQ ID NO:27, respectively; and q is an integer from 1 to 10, e.g., 1 or 10. In some aspects q is an integer from 2 to 5.In some aspects, q is an integer from 3 to 4.

[0226] In certain aspects, for AMCs of the 15thspecific aspect, the a biparatopic anti-FRa antibody or antigen-binding fragment thereof comprises polypeptides having the amino acid sequences of SEQ ID NOs: 30, 31, and 32.

[0227] In certain aspects, for compositions (e.g. , pharmaceutical compositions) comprising AMCs of the 15thspecific aspect, DAR is in the range of 3.0 to 4.0, 3.2 to 3.8, 3.1 to 3.7, or 3.4 to 3.7. In some aspects, the DAR is 3.2, 3.3, 3.4, 3.5, 3.5, 3.7, or 3.8. In some aspects, the DAR is 3.5.

[0228] In certain aspects, for compositions comprising lysine conjugates, DAR is in the range of 1.5 to 3.1. In some aspects, the DAR is about 2.0.

[0229] In some aspects, an AMC for use herein is IMGN151.IMGC936 and Related AMCs

[0230] In a first embodiment, the AMC for use herein comprises an anti-ADAM9 antibody or an ADAM9-binding fragment thereof described herein covalently linked to a maytansinoid compound described herein through the s-amino group of one or more lysine residues located on the anti-ADAM9 antibody or an ADAM9-binding fragment thereof or through the thiol group of one or more cysteine residues located on the anti-ADAM9 antibody or an ADAM9-binding fragment thereof.

[0231] In a 1stspecific embodiment of the first embodiment, the ADAM9 AMC for use herein is represented by formula (I) described above, wherein Rx, Ry, Rxand Ryare all H; and 1 and k are each independently an integer an integer from 2 to 6; and the remaining variables are as described above for formula (I).

[0232] In a 2ndspecific embodiment of the first embodiment, the ADAM9 AMC for use herein is represented by formula (I) described above, wherein A is a peptide containing 2 to 5 amino acid residues; and the remaining variables are as described above for formula (I) or in the 1stspecific embodiment. In some embodiments, A is a peptide cleavable by a protease. In some embodiments, a peptide cleavable by a protease expressed in tumor tissue. In some embodiments, A is a peptide having an amino acid that is covalent linked with -NH-CR1R2-S- Li-D selected from the group consisting of Ala, Arg, Asn, Asp, Cit, Cys, selino-Cys, Gin, Glu, Gly, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Vai, each independently as L or D isomer. In some embodiments, the amino acid connected to -NH-CR1R2-S-LI-D is an L amino acid.

[0233] In a 3rdspecific embodiment of the first embodiment, the ADAM9 AMC for use herein is represented by formula (I) described above, wherein A is selected from the group consisting of Gly-Gly-Gly, Ala-Vai, Vai-Ala, D-Val-Ala, Val-Cit, D-Val-Cit, Val-Lys, Phe- Lys, Lys-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Phe-Ala, Phe-N9-tosyl-Arg, Phe-N9-nitro- Arg, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Ala-Ala, D-Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala-D-Ala, Ala-Leu-Ala-Leu (SEQ ID NO: 52), p-Ala-Leu-Ala-Leu (SEQ ID NO:53), Gly-Phe-Leu-Gly (SEQ ID NO:54), Val-Arg, Arg- Arg, Val-D-Cit, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val-D-Cit, D-Val-D-Lys, D-Val-D-Arg, D-Arg-D-Arg, Ala-Ala, Ala-D-Ala, D-Ala-Ala, D-Ala-D-Ala, Ala- Met, Gln-Val, Asn-Ala, Gln-Phe, Gin-Ala, D-Ala-Pro, and D-Ala-tBu-Gly, wherein the first amino acid in each peptide is connected to L2 group and the last amino acid in each peptide is connected to -NH-CR1R2-S-L1-D; and the remaining variables are as described for formula (I) or in the 1stspecific embodiment.

[0234] In a 4thspecific embodiment of the first embodiment, the ADAM9 AMC for use herein is represented by formula (I) described above, wherein R1and R2are both H; and the remaining variables are as described for formula (I) or in the 1st, 2nd, or 3rdspecific embodiment.

[0235] In a 5thspecific embodiment of the first embodiment, the ADAM9 AMC for use herein is represented by formula (I) described above, wherein Li is -(CH2)4-6-C(=O)-; and the remaining variables are as described for formula (I) or in the 1st, 2nd, 3rdor 4thspecific embodiment.

[0236] In a 6thspecific embodiment of the first embodiment, the ADAM9 AMC for use herein is represented by formula (I) described above, wherein D is represented by the following formula:and the remaining variables are as described for formula (I) or in the 1st, 2nd, 3rd, 4thor 5thspecific embodiment.

[0237] In a 7thspecific embodiment, the ADAM9 AMC for use herein is represented by the following formula:or a pharmaceutically acceptable salt thereof, wherein:anti-ADAM9 antibody or ADAM9-binding fragment thereof connected to the L2 group through a Cys thiol group;R3and R4are each independently H or Me; rl and tl are each independently an integer from 1 to 6; r2 and t2 are each independently an integer from 1 to 7; t3 is an integer from 1 to 12;Di is represented by the following formula:; and q is an integer from 1 to 20. In a more specific embodiment, Di is represented by the following formula:

[0238] In an 8thspecific embodiment, the ADAM9 AMC for use herein is represented by the following formula:wherein: rl is an integer from 2 to 6; r2 is an integer from 2 to 5; and the remaining variables are as described in the 7thspecific embodiment.

[0239] In a 9thspecific embodiment, for the ADAM9 AMC for use herein in the 7thor 8thspecific embodiment, A is Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala, D-Ala-Ala, Vai-Ala, D-Val-Ala, D-Ala-Pro, or D-Ala-tBu-Gly. In a more specific embodiment, for the ADAM9 AMCs for use in the 7thor 8thspecific embodiment, A is L-Ala-D-Ala-L-Ala.

[0240] In a 10thspecific embodiment, the ADAM9 AMC for use herein is represented by the following formula:or a pharmaceutically acceptable salt thereof, wherein:A is Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala, D-Ala-Ala, Vai-Ala, D-Val-Ala,D-Ala-Pro, or D-Ala-tBu-Gly, andDi is represented by the following formula:and the remaining variables are as described in the 7th, 8thor 9thspecific embodiment. In a more specific embodiment, A is L-Ala-D-Ala-L-Ala. In a more specific embodiment, Di is represented by the following formula:

[0241] In a 11thspecific embodiment, the ADAM9 AMC for use herein is represented by the following formula:wherein Di is represented by the following formula:

[0242] In a 12thspecific embodiment, ADAM9 AMC for use herein is represented by the following formula:wherein:CBA is an humanized anti-ADAM9 antibody or ADAM9-binding fragment thereof comprising a CDRHI domain, a CDRH2 domain, and a CDRH3 domain and a CDRLI domain, a CDRL2 domain, and a CDRL3 domain having the sequences of SEQ ID NOs: 20-22 and SEQ ID NOs: 17-19, respectively; q is 1 or 2;Di is represented by the following formula:

[0243] In some embodiments, the humanized anti-ADAM9 antibody or ADAM9-binding fragment thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL) having sequences of SEQ ID NO:28 and SEQ ID NO:25, respectively. In some embodiments, the humanized anti-ADAM9 antibody comprises a heavy chain and a light chain having the sequences of SEQ ID NO:36 and SEQ ID NO:34, respectively.

[0244] In a 13thembodiment, the ADAM9 AMC for use herein comprises an anti-ADAM9 antibody, hMAB-A(2I.2)(YTE / C / -K)), coupled to a maytansinoid compound DM21C (also referred to as Mal-LDL-DM or MalC5-LDL-DM) represented by the following structural formula:wherein Di is represented by the following formula:The anti-ADAM9 antibody hMAB-A(2I.2)(YTE / C / -K)) has a heavy chain and a light chain having the sequences of SEQ ID NO:36 and SEQ ID NO:34, respectfully. In some embodiments, the ADAM9 AMC is referenced herein as hMAB-A(2I.2)(YTE / C / -K)-Mal- LDL-DM.

[0245] In one embodiment, the ADAM9 AMC hMAB-A(2I.2)(YTE / C / -K)-Mal-LDL-DM is represented by the following structural formula:wherein:CBA is the anti-ADAM9 antibody hMAB-A(2I.2)(YTE / C / -K) connected to the maytansinoid compound through a Cys thiol group; andq is 1 or 2.

[0246] In certain embodiments, for compositions (e.g., pharmaceutical compositions) comprising ADAM9 AMCs of the 13thspecific embodiment, DAR is in the range of 1.5 to 2.2, 1.7 to 2.2 or 1.9 to 2. 1. In some embodiment, the DAR is 1.7, 1.8, 1.9, 2.0 or 2. 1.via y-maleimidobutyric acid N-succinimidyl ester (GMBS) or a N- (y-maleimidobutryloxy)sulfosuccinimide ester (sulfo-GMBS or sGMBS) linker. The anti- ADAM9 antibody hMAB-A(2I.2)(YTE / -K))has a heavy chain and a light chain having the sequences of SEQ ID NO:36 and SEQ ID NO:24, respectfully.

[0247] The GMBS and sulfo-GMBS (or sGMBS) linkers are known in the art and can be presented by the following structural formula:

[0248] In some embodiments, the DAR is 3.2, 3.3, 3.4, 3.5, 3.5, 3.7, or 3.8.

[0249] In certain embodiments, for compositions (e.g., pharmaceutical compositions) comprising ADAM9 AMCs of the first embodiment, or the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, or 13thspecific embodiment, the average number of the cytotoxic agent per antibody molecule (z.e., average value of q), also known as Drug -Antibody Ratio (DAR) in the composition is in the range of 1.0 to 8.0. In some embodiments, DAR is in the range of 1.0 to 5.0, 1.0 to 4.0, 1.5 to 4.0, 2.0 to 4.0, 2.5 to 4.0, 1.0 to 3.4, 1.0 to 3.0, 2.9 to 3.3, 3.3 to 3.8, 1.5 to 2.5, 2.0 to 2.5, 1.7 to 2.3, or 1.8 to 2.2. In some embodiments, the DAR is less than 4.0, less than 3.8, less than 3.6, less than 3.5, less than 3.0 or less than 2.5. In some embodiments, the DAR is in the range of 3.2 to 3.4. In some embodiments, the DAR is in the range of 3.0 to 3.2.In some embodiments, the DAR is in the range of 3.5 to 3.7. In some embodiments, the DAR is 3.1, 3.2, 3.3, 3.4, 3.5, 3.6 or 3.7. In some embodiments, the DAR is in the range of 1.8 to 2.0. In some embodiments, the DAR is in the range of 1.7 to 1.9. In some embodiments, the DAR is in the range of 1.9 to 2.1. In some embodiments, the DAR is 1.9, 2.0 or 2.1. In some embodiments, for the ADAM9 AMCs comprising an anti-ADAM9 antibody or an anti- ADAM9-binding fragment thereof linked to the maytansinoid compound through one or more cysteine thiol group, the DAR is in the range of 1.5 to 2.5, 1.8 to 2.2, 1.1 to 1.9 or 1.9 to 2.1. In some embodiments, the DAR is 1.8, 1.9, 2.0 or 2. 1.

[0250] In some aspects, an AMC for use herein is IMGC936.V. Composition and Kits

[0251] Provided herein are compositions comprising an AMC or vasoconstrictor described herein having the desired degree of purity in a physiologically acceptable carrier, excipient or stabilizer (Remington’s Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA). Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed.

[0252] A pharmaceutical composition may be formulated for a particular route of administration to a subject. For example, a pharmaceutical composition comprising an AMC can be formulated for parenteral, e.g., intravenous, administration. The compositions to be used for in vivo administration can be sterile. This is readily accomplished by filtration through, e.g., sterile filtration membranes. A pharmaceutical composition comprising a vasoconstrictor can be formulated for topical administration, e.g., via an eye drop.

[0253] The pharmaceutical compositions described herein are in one aspect for use as a medicament. Pharmaceutical compositions comprising AMCs described herein can be useful in treating a condition such as cancer. Examples of cancer that can be treated as described herein include, but are not limited to ovarian cancer (e.g., epithelial ovarian cancer), peritoneal cancer (primary peritoneal cancer), fallopian tube cancer, endometrial cancer, lung cancer (e.g., non-squamous non-small cell lung cancer), breast cancer (e.g., triple negative breast cancer), gastroesophageal cancer, colorectal cancer, and pancreatic cancer

[0254] Pharmaceutical compositions comprising vasoconstrictors described herein can be useful in reducing ocular toxicity associated with an AMC.

[0255] A pharmaceutical composition provided herein can comprise AMCs and the pharmaceutical composition (AMCs in the pharmaceutical composition) can have an averageof 1 to 20 drugs per biparatopic antibody or antigen-binding fragment thereof. In some aspects, a pharmaceutical composition comprising AMCs comprises an average of 1 to 10 drugs per antibody or antigen-binding fragment thereof. In some aspects, a pharmaceutical composition comprising AMCs comprises an average of 2 to 5 drugs per antibody or antigen-binding fragment thereof. In some aspects, a pharmaceutical composition comprising AMCs comprises an average of 3 to 4 drugs per biparatopic antibody or antigen-binding fragment thereof.VI. Methods and Uses

[0256] In some aspects, the disclosure provides a method of administering an antibody maytansinoid conjugate (AMC) to a patient in need thereof that comprises administering an effective amount of a vasoconstrictor and an effective amount of the AMC to the patient, wherein the vasoconstrictor is administered prior to, during, and / or after the AMC is administered to the patient. In some embodiments, the vasoconstrictor is administered after the administration of the AMC to the patient. In some embodiments, the vasoconstrictor is administered prior to the administration of the AMC to the patient. In some embodiments, the vasoconstrictor is administered during the administration of the AMC to the patient. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day at least 2,3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the at least 2, 3,4, 5, 6, 7, 8, or 14 days, are consecutive days, respectively, after the administration of the vasoconstrictor. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day at least 2, 3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the at least 2, 3, 4, 5, 6, 7, 8, or 14 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day at least 2, 3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the 2, 3, 4, 5, 6, 7, 8, or 14 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, the provided method reduces ocular toxicity. In some embodiments, the method results in a reduction in the frequency of Grade 3 or higher ocular toxicity. In some embodiments, the method results in at least 10%, 20%, 30%, 40% or 50% reduction in the frequency of Grade 3 or higher ocular toxicity. In some embodiments, the method results in a reduction in the frequency of Grade 2 or higher ocular toxicity. In some embodiments, the method results in at least 10%, 20%, 30%, 40% or 50% reduction in the frequency of Grade 2 or higher ocular toxicity. In some embodiments, themethod results in a reduction in the frequency of one or more ocular toxicities to less than 40%, 30% 20% or 10%.

[0257] In some aspects, the disclosure provides a method of reducing ocular toxicity associated with the administration of an AMC to a patient, which comprises administering an effective amount of a vasoconstrictor to the patient after the patient has been treated with the AMC. In further embodiments, the vasoconstrictor has been administered prior to the administration of the AMC to the patient. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day at least 2, 3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the at least 2, 3, 4, 5, 6, 7, 8, or 14 days, are consecutive days, respectively, after the administration of the vasoconstrictor. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day at least 2,3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the at least 2, 3,4, 5, 6, 7, 8, or 14 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day at least 2, 3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the 2, 3, 4, 5, 6, 7, 8, or 14 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, the method results in a reduction in the frequency of Grade 3 or higher ocular toxicity. In some embodiments, the method results in at least 10%, 20%, 30%, 40% or 50% reduction in the frequency of Grade 3 or higher ocular toxicity. In some embodiments, the method results in a reduction in the frequency of Grade 2 or higher ocular toxicity. In some embodiments, the method results in at least 10%, 20%, 30%, 40% or 50% reduction in the frequency of Grade 2 or higher ocular toxicity. In some embodiments, the method results in a reduction in the frequency of one or more ocular toxicities to less than 40%, 30% 20% or 10%.

[0258] In some aspects, the disclosure provides a method of treating ocular toxicity associated with the administration of an AMC to a patient, which comprises administering an effective amount of a vasoconstrictor to the patient after the patient has been treated with the AMC. In further embodiments, the vasoconstrictor has been administered prior to the administration of the AMC to the patient. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day at least 2, 3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the at least 2, 3, 4, 5, 6, 7, 8, or 14 days, are consecutive days, respectively, after the administration of the vasoconstrictor. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day at least 2,3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the at least 2, 3,4, 5, 6, 7, 8, or 14 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, the vasoconstrictor is administered 1, 2, 3, 4, 5, or more times a day at least 2, 3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the 2, 3, 4, 5, 6, 7, 8, or 14 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, the provided method reduces ocular toxicity. In some embodiments, the method results in a reduction in the frequency of Grade 3 or higher ocular toxicity. In some embodiments, the method results in at least 10%, 20%, 30%, 40% or 50% reduction in the frequency of Grade 3 or higher ocular toxicity. In some embodiments, the method results in a reduction in the frequency of Grade 2 or higher ocular toxicity. In some embodiments, the method results in at least 10%, 20%, 30%, 40% or 50% reduction in the frequency of Grade 2 or higher ocular toxicity. In some embodiments, the method results in a reduction in the frequency of one or more ocular toxicities to less than 40%, 30% 20% or 10%.

[0259] As provided herein, a vasoconstrictor and an AMC can be used for a variety of applications including, but not limited to, therapeutic treatment methods, such as the treatment of cancer while reducing ocular toxicity.

[0260] In some aspects, the disclosure provides a method for safely and effectively treating cancer in a patient, which comprises (a) intravenously administering a therapeutically effective amount of an AMC to the patient; and (b) topically administering a vasoconstrictor to at least one eye of the patient after the administration of the AMC. In some embodiments, the vasoconstrictor is administered at least 2, 3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the at least 2, 3, 4, 5, 6, 7, 8, or 14 days, are consecutive days, respectively, after the administration of the vasoconstrictor. In some embodiments, the vasoconstrictor is administered at least 2, 3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the at least 2, 3, 4, 5, 6, 7, 8, or 14 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, the vasoconstrictor is administered 2, 3, 4, 5, 6, 7, 8, or 14 days after administration of the AMC, optionally where the 2, 3, 4, 5, 6, 7, 8, or 14 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, when the method is used to treat cancer in a population of patients, the method results in a reduction in the frequency of one or more ocular toxicity compared to an identical method practiced without the step of administering the vasoconstrictor.

[0261] In some aspects, the disclosure provides a method for safely and effectively treating cancer in a patient with an AMC delivered to the patient intravenously, which comprisestopically administering a vasoconstrictor to at least one eye of the patient after the administration of the AMC. In some embodiments, the vasoconstrictor is administered at least 2, 3, 4, 5, 6, 7, 8, 14, 21, or 28 days after administration of the AMC, optionally where the at least 2, 3, 4, 5, 6, 7, 8, 14, 21, or 28 days, are consecutive days, respectively, after the administration of the vasoconstrictor. In some embodiments, the vasoconstrictor is administered at least 2, 3, 4, 5, 6, 7, 8, 14, 21, or 28 days after administration of the AMC, optionally where the at least 2, 3, 4, 5, 6, 7, 8, 14, 21, or 28 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, the vasoconstrictor is administered 2, 3, 4, 5, 6, 7, 8, 14, 21, or 28 days after administration ofthe AMC, optionally where the 2, 3, 4, 5, 6, 7, 8, 14, 21, or 28 days are consecutive days, respectively, after the administration of the AMC. In some embodiments, when the method is used to treat cancer in a population of patients the method results in a reduction in the frequency of one or more ocular toxicity compared to an identical method practiced without the step of administering the vasoconstrictor. In further embodiments, the identical method practiced without the step of administering the vasoconstrictor further comprises administering a steroid eye drop to at least one eye of the patient after the administration of the AMC. In some embodiments, the steroid eye drop comprises prednisolone.

[0262] In some aspects, the cancer is in a human subject. In some aspects, the cancer is selected from the group consisting of ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, breast cancer, gastroesophageal cancer, colorectal cancer, and pancreatic cancer. In some aspects, the cancer is ovarian cancer, e.g., epithelial ovarian cancer. In some aspects, the cancer is peritoneal cancer, e.g., primary peritoneal cancer. In some aspects, the cancer is lung cancer, e.g., non-squamous non-small cell lung cancer. In some aspects, the cancer is breast cancer, e.g., triple negative breast cancer.

[0263] As provided herein, a patient treated with a vasoconstrictor and an AMC can be a patient without ocular symptoms. In some aspects, the patient treated with a vasoconstrictor and an AMC is a patient at risk of developing one or more ocular symptoms. In some aspects, a vasoconstrictor is administered to a patient with the first administration of the AMC to the patient.

[0264] As provided herein, a patient treated with a vasoconstrictor and an AMC can be a patient with ocular symptoms, e.g., > Grade 2 ocular system, at the time of the administration. For example, a patient treated with a vasoconstrictor and an AMC can be a patient with comeal microsyst-like epithelial keratopathy, e.g., > Grade 2 comeal microsyst-like epithelial keratopathy.

[0265] In some aspects, the ocular symptom is a corneal condition or disorder. In some aspects, the ocular symptom is a > Grade 2 corneal condition or disorder. In some aspects, the ocular symptom is a > Grade 3 comeal condition or disorder. In some aspects, the ocular symptom is punctate keratitis, for example, superficial keratitis, superficial punctate keratitis, or punctate epithelial erosion. In some aspects, the ocular symptom is nonconfluent keratitis. In some aspects, the ocular symptom is confluent keratitis. In some aspects, the ocular symptom is keratopathy, for example, microcystic epithelial change, non-staining punctate epithelial keratopathy, or subepithelial inclusion cyst. In some aspects, the ocular symptom is nonconfluent keratopathy. In some aspects, the ocular symptom is confluent keratopathy. In some aspects, the ocular symptom is cornea epithelial defect. In some aspects, the ocular symptom is comeal ulcer. In some aspects, the ocular symptom is cornea stromal opacity. In some aspects, the ocular symptom is comeal perforation. In certain aspects, the ocular symptom does not comprise cornea stromal opacity. In certain aspects, the ocular symptom does not comprise cornea subepithelial opacity.Methods and Uses for Vasoconstrictors with AMCs That Bind to FRq

[0266] A vasoconstrictor and an AMC that binds to FRa can be used to treat a cancer, e.g., an FRa-expressing cancer, while reducing ocular toxicity associated with the AMC.

[0267] In some aspects, the cancer treated with a vasoconstrictor and an AMC that binds to FRa is epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In some aspects, the cancer is recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In some aspects, the cancer is a FRa positive platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, wherein the cancer has been treated with one to three prior systemic treatment regimens.

[0268] As provided herein, a vasoconstrictor and an AMC that binds to FRa can be administered to a patient with increased expression of FRa, for example, as described in PCT Publication No. WO 2012 / 135675, WO 2015 / 031815, and / or WO 2022 / 256507, each of which is herein incorporated by reference in its entirety. In some aspects, the FRa protein expression is measured by immunohistochemistry (IHC) and given a staining intensity score and / or a staining uniformity score by comparison to controls (e.g., calibrated controls) exhibiting defined scores (e.g. an intensity score of 3 is given to the test sample if the intensity is comparable to the level 3 calibrated control or an intensity of 2 (moderate) is given to the test sample if the intensity is comparable to the level 2 calibrated control). A staining uniformity that is "heterogeneous" (i.e., at least 25% and less than 75% cells stained) or "homogeneous"(i.e., at least 75% cells stained) instead of "focal" (i.e., greater than 0% and less than 25% cells stained) is also indicative of increased FRa expression. The staining intensity and staining uniformity scores can be used alone or in combination (e.g., 2 homo, 2 hetero, 3 homo, 3 hetero, etc.). In another example, an increase in FRa expression can be determined by detection of an increase of at least 2-fold, at least 3-fold, or at least 5-fold) relative to control values (e.g., expression level in a tissue or cell from a subject without cancer or with a cancer that does not have elevated FRa values). In some aspects, the staining uniformity score is based on the percent of stained cells.

[0269] In some aspects, the cancer is a cancer that expresses FRa at a level of 1 hetero or higher by IHC. In some aspects, the cancer is a cancer that expresses FRa at a level of 2 hetero or higher by IHC. In some aspects, the cancer is a cancer that expresses FRa at a level of 3 hetero or higher by IHC. In some aspects, the cancer is a lung cancer that expresses FRa at a level of 2 hetero or higher by IHC. In some aspects, the cancer is a lung cancer that expresses FRa at a level of 3 hetero or higher by IHC. In some aspects, the cancer is an ovarian cancer that expresses FRa at a level of 2 hetero or higher by IHC. In some aspects, the cancer is an ovarian cancer that expresses FRa at a level of 3 hetero or higher by IHC. In some aspects, the cancer is an endometrial cancer that expresses FRa at a level of 2 hetero or higher by IHC. In some aspects, the cancer is an endometrioid cancer that expresses FRa at a level of 1 hetero or higher by IHC.

[0270] In some aspects, at least one cell in sample obtained from a patient has an FRa score of at least 1. In some aspects, at least one cell in sample obtained from a patient has an FRa score of at least 2 (moderate). In some aspects, at least one cell in sample obtained from a patient has an FRa score of at least 3.

[0271] In some aspects, at least 25% of the cells in a sample obtained from a patient have a FRa IHC score of at least 1. In some aspects, at least 33% of the cells in a sample obtained from a patient have a FRa IHC score of at least 1. In some aspects, at least 50% of the cells in a sample obtained from a patient have a FRa IHC score of at least 1. In some aspects, at least 66% of the cells in a sample obtained from a patient have a FRa IHC score of at least 1. In some aspects, at least 75% of the cells in a sample obtained from a patient have a FRa IHC score of at least 1.

[0272] In some aspects, at least 25% of the cells in a sample obtained from a patient have a FRa IHC score of at least 2 (moderate). In some aspects, at least 33% of the cells in a sample obtained from a patient have a FRa IHC score of at least 2 (moderate). In some aspects, 25- 75% of the cells in a sample obtained from a patient have a FRa IHC score of at least 2(moderate). In some aspects, at least 50% of the cells in a sample obtained from a patient have a FRa IHC score of at least 2 (moderate). In some aspects, at least 66% of the cells in a sample obtained from a patient have a FRa IHC score of at least 2 (moderate). In some aspects, at least 75% of the cells in a sample obtained from a patient have a FRa IHC score of at least 2 (moderate).

[0273] In some aspects, at least 25% of the cells in a sample obtained from a patient have a FRa IHC score of at least 3. In some aspects, at least 33% of the cells in a sample obtained from a patient have a FRa IHC score of at least 3. In some aspects, at least 50% of the cells in a sample obtained from a patient have a FRa IHC score of at least 3. In some aspects, at least 66% of the cells in a sample obtained from a patient have a FRa IHC score of at least 3. In some aspects, at least 75% of the cells in a sample obtained from a patient have a FRa IHC score of at least 3.

[0274] In some aspects, FRa expression can be measured by immunohistochemistry and given a visual score where FRa positive may refer to greater than or equal to 50% of tumor cells with FRa membrane staining visible at less than or equal to 10X microscope objective. In some aspects, FRa expression can be measured by immunohistochemistry and given a visual score where FRa positive may refer to greater than or equal to 66% of tumor cells with FRa membrane staining visible at less than or equal to 10X microscope objective. In some aspects, FRa expression can be measured by immunohistochemistry and given a visual score where FRa positive may refer to greater than or equal to 75% of tumor cells with FRa membrane staining visible at less than or equal to 10X microscope objective.

[0275] In some aspects, a vasoconstrictor and an AMC that binds to FRa are used to treat a patient with a soluble FRa level equal to or greater than a target soluble FRa level. In some aspects, a patient with a soluble FRa level equal to or greater than a target soluble FRa level also has increased expression of FRa as measured by immunohistochemistry. In some aspects, a patient with a soluble FRa level equal to or greater than a target soluble FRa level does not have increased expression of FRa as measured by immunohistochemistry.

[0276] In some aspects herein, wherein a vasoconstrictor and an AMC that binds to FRa are used to treat cancer, the AMC that binds to FRa is administered in a three-week cycle (Q3W). In some aspects, the AMC that binds to FRa is administered at a dose of 6 mg / kg adjusted ideal body weight (AIBW; also referred to as adjusted body weight (ADJ)). AIBW is calculated using the formula AIBW = IBW + 0.4(weight in kg- IBW), wherein IBW (i.e., ideal body weight) = 0.9H-88 (for males) and IBW = 0.9H-92 (for females), wherein H=height in cm. In some aspects, the AMC that binds to FRa is administered at a dose of 5 mg / kg AIBW.In some aspects, the AMC that binds to FRa is administered at a dose of 6 mg / kg AIBW every three weeks. In some aspects, the AMC that binds to FRa is administered at a dose of 5 mg / kg AIBW every three weeks.Methods and Uses for Vasoconstrictors with AMCs That Bind to ADAM9

[0277] A vasoconstrictor and an AMC that binds to ADAM9 can be used to treat a cancer, e.g., an ADAM9-expressing cancer, while reducing ocular toxicity associated with the AMC.

[0278] In some aspects, the cancer treated with a vasoconstrictor and an AMC that binds to ADAM9 can be used to treat non-squamous non-small cell lung cancer, triple -negative breast cancer, gastroesophageal cancer, colorectal cancer, or pancreatic cancer.

[0279] As provided herein, a vasoconstrictor and an AMC that binds to ADAM9 can be administered to a patient with increased expression of ADAM9, for example, as described in PCT Publication No. WO 2022 / 192134, which is herein incorporated by reference in its entirety. PCT Publication No. WO 2022 / 192134 provides, for example, methods of determining an Id-score for an ADAM9-expressing cancer. In some aspects, the cancer to be treated according to the methods provided herein has an Id-score of about 50 to about 300 or of about 100 to about 300. PCT Publication No. WO 2022 / 192134 also provides, for example, methods of determining an H score for an ADAM9-expressing cancer. In some aspects, the cancer to be treated according to the methods provided herein has an H-score of about 201 to about 300, of about 101 and about 200, or of about 1 to about 100. PCT Publication No. WO 2022 / 192134 further provides, for example, methods of determining an IHC intensity score for an ADAM9-expressing cancer. In some aspects, the cancer to be treated according to the methods provided herein has an IHC intensity score of 2 or greater. In some aspects, the cancer to be treated according to the methods provided herein has an IHC intensity score of 3 or greater. PCT Publication No. WO 2022 / 192134 further provides, for example, methods of determining a PS value for an ADAM9-expressing cancer. In some aspects, the cancer to be treated according to the methods provided herein has staining of 25% or greater PSI, 50% or greater PS 1, or 75% or greater PS 1. In some aspects, the cancer to be treated according to the methods provided herein has about 25 to about 49%, about 50 to about 74%, or about 75 to about 100% PS 1. In some aspects, the cancer to be treated according to the methods provided herein has staining of 25% or greater PS 2, 50% or greater PS 2, or 75% or greater PS 2. In some aspects, the cancer to be treated according to the methods provided herein has about 25 to about 49%, about 50 to about 74%, or about 75 to about 100% PS 2. In some aspects, the cancer to be treated according to the methods provided herein has staining of 25% or greaterPS 3, 50% or greater PS 3, or 75% or greater PS 3. In some aspects, the cancer to be treated according to the methods provided herein has about 25 to about 49%, about 50 to about 74%, or about 75 to about 100% PS 3.VII. Additional Therapies

[0280] In some aspects, a method of treatment provided herein comprises administering a vasoconstrictor, an AMC, and at least one topical ocular agent.

[0281] In some aspects, the at least one topical agent is a steroid eye drop. In some aspects, the at least one topical agent is a corticosteroid eye drop. In some aspects, the at least one topical agent is prednisolone. In some aspects, the at least one topical agent is difluprednate. A steroid, corticosteroid, prednisolone, or difluprednate can be administered, e.g., about one to about ten times per day. For example, a corticosteroid, prednisolone, or difluprednate can be administered two, three, four, five, or six times per day. In some aspects, a steroid, corticosteroid, prednisolone, or difluprednate is administered four times per day. In some aspects, a steroid, corticosteroid, prednisolone, or difluprednate is administered six times per day. In some aspects, a steroid, corticosteroid, prednisolone, or difluprednate is administered six times per day for a series of days (e.g., about two to about five days, e.g., about four days) and then administered four times per day for a series of days (e.g., about two to about five days, e.g., about four days).

[0282] In some aspects, the at least one topical agent is cyclosporine eye drops, e.g., 0.025% - 0.2% cyclosporine eye drops. In some aspects, cyclosporine eye drops are administered for at least two days or at least three days. In some aspects, cyclosporine eye drops are administered throughout the cycle of administration of an AMC.

[0283] In some aspects, the at least one topical agent is a lubricating eye drop. The lubricating eye drop can be administered after the administration of the vasoconstrictor. For example, the lubricating eye drop can be administered about 10 minutes to about an hour after administration of the vasoconstrictor. The lubricating eye drop can be administered about 10 minutes to about 30 minutes after administration of the vasoconstrictor. The lubricating eye drop can be administered about 15 minutes after administration of the vasoconstrictor. Lubricating eye drops can be administered, e.g., about one to about ten times per day.Lubricating eye drops can be administered, e.g., about two to about ten times per day.Lubricating eye drops can be administered, e.g., about three to about ten times per day.Lubricating eye drops can be administered, e.g., about four to about ten times per day. Forexample, lubricating eye drops can be administered about two, three, four, five, or six times per day. In some aspects, lubricating eye drops are administered about three times per day. In some aspects, lubricating eye drops are administered about four times per day. In some aspects, lubricating eye drops are administered at least two, at least three, or at least four times per day. Lubricating eye drops can be administered throughout the cycle of administration of an AMC. Lubricating eye drops can be administered before administration of the AMC on day 1 of a treatment cycle. Lubricating eye drops can be administered after the administration of the AMC on day 1 of a treatment cycle. Lubricating eye drops can be administered after the administration of the AMC on day 1 of a treatment cycle and every day during the entire cycle of treatment (e.g., on day 2, day 3, day 4, day 5, day 6, day 7, up to day 21 or 28). Lubricating eye drops can be administered no more than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours after the administration of the AMC on day 1 of a treatment cycle. Lubricating eye drops can be administered no more than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours after the administration of the AMC on day 1 of a treatment cycle and every day during the entire cycle of treatment (e.g., on day 2, day 3, day 4, day 5, day 6, day 7, up to day 21 or 28). In some aspects, lubricating eye drops are administered about four times per day.

[0284] In some aspects, each of the (i) vasoconstrictor, (ii) steroid, corticosteroid, prednisolone, or difluprednate, (iii) cyclosporine eye drops, and / or (iv) lubricating eye drops are administered at least 10 minutes apart from each other. In some aspects, each of the (i) vasoconstrictor, (ii) steroid, corticosteroid, prednisolone, or difluprednate, (iii) cyclosporine eye drops, and / or (iv) lubricating eye drops are administered at least 15 minutes apart from each other. In some aspects, each of (i) vasoconstrictor, (ii) steroid, corticosteroid, prednisolone, or difluprednate, (iii) cyclosporine eye drops, and / or (iv) lubricating eye drops are administered about 10 minutes to about 1 hour apart from each other.

[0285] Aspects of the present disclosure can be further defined by reference to the following non-limiting examples, which describe in detail preparation of certain antibodies of the present disclosure and methods for using antibodies of the present disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure.EXAMPLES

[0286] It is understood that the examples and aspects described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application.Example 1. Ocular Distribution and Pharmacokinetics Study Following a 30-Minute Intravenous Infusion of IMGN853 (M-sulfo-SPDB-3H-DM4) or M-SPDB-3H-DM4 to Male Pigmented Rabbits

[0287] Rabbits were assigned to two groups for this study. At designated times following dosing, blood and ocular tissues were collected. The group designations, number of animals, target dose level, and target dose volume were as follows:IV Intravenous infusion (approximately 30 minutes).Note: The mean dose of radioactivity administered was 85.7 and 103 pCi / kg for Groups1 and 2, respectively. a Three animals / group were euthanized at each designated time point.

[0288] The purpose of this study was to assess the ocular distribution and pharmacokinetics after a 30-minute intravenous infusion of M-sulfo-SPDB-3H-DM4 (IMGN853) or M-SPDB-3H-DM4 (test articles) to male pigmented rabbits via an indwelling ear vein catheter. Animals were not fasted prior to dose administration. The volume of radiolabeled dose formulation to be administered to each animal was calculated based on the body weight taken on the day of dose administration. The actual amount administered was determined by weighing the dose syringe before and after dose administration. A board-certified veterinary ophthalmologist conducted ophthalmic examinations pre-dose and on Study Days 5, 8, and 15, prior to sacrifice, as applicable. Both eyes were examined using a slitlamp biomicroscope. In addition, the eyes were dilated with a mydriatic agent and examined using an indirect ophthalmoscope. Followingthe test article administration, blood, plasma, and ocular tissues were collected at various time points through 336 hours post-dose for radioanalysis. Animals were euthanized with sodium pentobarbital, and blood was collected via cardiac puncture from three animals / group / time point at 1, 24, 48, 96, 168, and 336 hours post-dose. One left eye / group / time point was used for microautoradiography (MARG). Selected ocular tissues from three right eyes / group / time point were collected for radioanalysis.Group 1

[0289] A single intravenous infusion at 12 mg / kg, M-sulfo-SPDB-3H-DM4 (IMGN853) was well-tolerated, and all animals appeared generally healthy and exhibited no overt signs of toxicity for the duration of the study. The concentration versus time profiles were very similar between blood and plasma, resulting in pharmacokinetic parameters which were also very similar. The blood and plasma concentrations of radioactivity were highest at 1 hour postdose (Tmax), the earliest time point, and declined at later time points but were quantifiable throughout the duration of the study (336 hours postdose). The mean Cmax values for blood and plasma were 155,000 ± 6,250 and 178,000 ± 16,500 ng equivalents M-sulfo-SPDB-3H-DM4 / g, respectively. The calculated half-life (ti / 2) values of total radioactivity in blood and plasma for Group 1 were 98.5 and 94.0 hours, respectively. The extrapolated exposures (AUCo-®) of radioactivity in blood and plasma were 9,720,000 and 11,100,000 ng equivalents M-sulfo- SPDB-3H-DM4 hr / g, respectively. The mean blood to plasma concentration ratios ranged from 0.812 to 0.952, indicating no preferential association of radioactivity with the cellular component of blood. At each time point, aliquots of collected plasma were dried to assess tritiated water loss, and also extracted with acetone to assess the free3H-DM4 present. The concentration versus time profile for dried plasma was very similar to plasma in shape and magnitude, thus the pharmacokinetic parameters were nearly equal. The mean dried plasma to plasma concentration ratios ranged from 0.875 to 1.14, further illustrating the similarity. The mean percent of the tritiated water was the highest (12.5%) at 1 hour postdose, but was never above 2% through the remainder of the study. The concentration versus time profile for plasma acetone extracts was similar to plasma in shape but nearly 2 orders lower in magnitude. The plasma acetone extractable percentage of radioactivity started low with 0.599% at 1 hour postdose, and then increased through 336 hours postdose to 2.32%. The observed plasma exposure (AUCo-t) to acetone extractable radioactivity was less than 1% of the AUCo-t of plasma. Taken together, these results suggest a moderate amount of tritiated water loss at thefirst time point, and a minor amount of acetone extractable radioactivity was present through 336 hours postdose; however, the majority of the Group 1 dosed radioactivity measured in plasma was intact M-sulfo-SPDB-3H-DM4.

[0290] Following intravenous infusion of M-sulfo-SPDB-3H-DM4 (12 mg / kg) to rabbits in Group 1, radioactivity in the peripheral ocular tissues (eyelid, bulbar conjunctiva, and nictitating membrane) generally displayed an absorption / distribution phase followed by a terminal elimination phase. The radioactivity concentrations peaked at 24 hours post-dose for these tissues, and declined steadily through the last quantifiable time point at 336 hours postdose. The mean Cmax values were 12,300, 16,900, and 12,800 equivalents M-sulfo-SPDB-3H-DM4 / g for the eyelids, bulbar conjunctiva, and nictitating membrane, respectively. The calculated half-life (ti / 2) values of total radioactivity in eyelids, bulbar conjunctiva, and nictitating membrane were 103, 120, and 78.2 hours, respectively. The extrapolated exposures (AUCO-M) of radioactivity in eyelids, bulbar conjunctiva, and nictitating membrane were 2,080,000, 2,700,000, and 1,980,000 ng equivalents M-sulfo-SPDB-3H-DM4 hr / g, respectively.

[0291] Following intravenous infusion of M-sulfo-SPDB-3H-DM4 (12 mg / kg) to rabbits in Group 1, the concentration versus time profiles were similar in the three layers of the cornea. The profile for each layer had an apparent absorption phase, followed by a relatively stable concentration plateau. The comeal layer concentrations of radioactivity were lowest at 1 hour post-dose, peaked at 48 or 96 hours postdose, then declined slightly while still quantifiable throughout the duration of the study (336 hours postdose). The mean Cmax concentrations of M-sulfo-SPDB-3H-DM4-derived radioactivity in the comeal endothelium, comeal stroma, and comeal epithelium were 4,570 ± 2,710, 3,690 ± 517, and 2,500 ± 525 ng equivalents M-sulfo- SPDB-3H-DM4 / g, respectively. The plateau of concentrations did not afford the calculation of other pharmacokinetic parameters such as half-life or AUCo- / . The observed exposures (AUCo- t) of radioactivity in the comeal endothelium, comeal stroma, and comeal epithelium were 827,000, 931,000, and 485,000 ng equivalents M-sulfo-SPDB-3H-DM4 hr / g, respectively. The mean comeal tissue to plasma concentration ratios started low and increased with time, ranging from 0.000524 to 0.468. These ratios indicated no preferential association or distribution of radioactivity to the cornea layers in Group 1.

[0292] Following intravenous infusion of M-sulfo-SPDB-3H-DM4 (12 mg / kg) to rabbits in Group 1, dmg -derived radioactivity proceeded to distribute within the anterior tissues along the conventional outflow pathway including the aqueous humor, limbal sclera, and the remaining sclera. A concentration gradient was present from the cornea and iris-ciliary body(ICB) towards the tissues along aqueous humor outflow pathway. Except for aqueous humor, the mean radioactivity concentrations of anterior tissues generally peaked at 24 hours postdose followed by a terminal elimination phase. Radioactivity was quantifiable through 336 hours postdose. The Group 1 ti / 2 values for the anterior tissues that could be calculated were similar to the radioactivity ti / 2 in blood and plasma of approximately 100 hours. The tissue to plasma ratios for anterior ocular tissues increased over time, and no preferential distribution was observed for M-sulfo-SPDB-3H-DM4.

[0293] Following intravenous infusion of M-sulfo-SPDB-3H-DM4 (12 mg / kg) to rabbits in Group 1, drug-derived radioactivity proceeded to distribute within the posterior tissues through the interior tissue layers of the eye including choroid-RPE, ICB, retina, optic nerve head, and optic nerve. Mean radioactivity concentrations generally peaked at 1 to 24 hours postdose and then displayed a distribution phase followed by a terminal elimination phase. The ti / 2 values which could be calculated were similar to the ti / 2 in blood and plasma of approximately 100 hours, except for optic nerve (147 hours) and optic nerve head (75.2 hours). Although the tissue to plasma ratios for posterior ocular tissues increased over time, no preferential distribution was observed for M-sulfo-SPDB-3H-DM4.

[0294] Following intravenous infusion of M-sulfo-SPDB-3H-DM4 at a dose level of 12 mg / kg to Group 1, there was moderate absorption and ocular distribution of radioactivity into the structures of the eye as assessed by microautoradiography (MARG). In general, there were more silver grains present at low levels in the eyes of the Group 1 animals that received M- sulfo-SPDB-3H-DM4. Most of the observed radioactivity was present in the eyes obtained from animals sacrificed at 1 and 24 hours postdose, with low levels associated with most regions (optic nerve, iris, ciliary body, choroid, sclera, and vitreous humor) at these times. By 48 hours, levels were decreased, and low levels were associated with the optic nerve and sclera. Radioactivity was associated with the cornea at early time points, but was at background levels at 96 hours postdose and beyond.Group 2

[0295] Following intravenous infusion of M-SPDB-3H-DM4 (12 mg / kg) to rabbits in Group 2, the concentration versus time profiles were very similar between blood and plasma, resulting in pharmacokinetic parameters which were also very similar. The blood and plasma concentrations of radioactivity were highest at 1 hour postdose (Tmax), the earliest time point, and declined at later time points but were quantifiable throughout the duration of the study (336hours postdose). The Group 2 mean Cmax values for blood and plasma were 158,000 ± 3,070 and 176,000 ± 14,400 ng equivalents M-SPDB-3H-DM4 / g, respectively. The calculated halflife (ti / 2) values of total radioactivity in blood and plasma for Group 2 were both 109 hours. The extrapolated exposures (AUCo-, ) of radioactivity in blood and plasma were 9,120,000 and 10,400,000 ng equivalents M-SPDB-3H-DM4 hr / g, respectively. The mean blood to plasma concentration ratios ranged from 0.826 to 0.913, indicating no preferential association of radioactivity with the cellular component of blood.

[0296] At each time point, aliquots of collected plasma were dried to assess tritiated water loss, and also extracted with acetone to assess the free3H-DM4 present. The concentration versus time profde for dried plasma was very similar to plasma in shape and magnitude, thus the pharmacokinetic parameters were nearly equal. The mean dried plasma to plasma concentration ratios ranged from 0.926 to 1.19, further illustrating the similarity. The mean percent of the plasma tritium loss of radioactivity was the highest (7.38%) at 1 hour postdose, but was never above 4% through the remainder of the study. The concentration versus time profde for plasma acetone extracts was similar to plasma in shape but nearly 2 orders lower in magnitude. The plasma acetone extractable percentage of radioactivity started low with 0.528% at 1 hour post-dose, and then increased through 336 hours post-dose to 1.65%. The observed plasma exposure (AUCo-t) to acetone extractable radioactivity was less than 1% of the AUCo-t of plasma. Taken together, these results suggest a moderate amount of tritiated water loss at the first time point, and a minor amount of acetone extractable radioactivity was present through 336 hours postdose; however, the majority of the Group 2 dosed radioactivity measured in plasma was intact M-SPDB-3H-DM4.

[0297] Following intravenous infusion of M-SPDB-3H-DM4 (12 mg / kg) to rabbits in Group 2, radioactivity in the peripheral ocular tissues (eyelid, bulbar conjunctiva, and nictitating membrane) generally displayed an absorption / distribution phase followed by a terminal elimination phase. The radioactivity concentrations peaked at 24 hours post-dose for these tissues, and declined steadily through the last quantifiable time point at 336 hours postdose. The mean Cmax values were 10,500, 14,800, and 12,000 equivalents M-SPDB-3H- DM4 / g for the eyelids, bulbar conjunctiva, and nictitating membrane, respectively. The calculated half-life (ti / 2) values of total radioactivity in eyelids, bulbar conjunctiva, and nictitating membrane were 105, 123, and 135 hours, respectively. The extrapolated exposures (AUCO-M) of radioactivity in eyelids, bulbar conjunctiva, and nictitating membrane were 1,970,000, 2,760,000, and 1,750,000 ng equivalents M-SPDB-3H-DM4 hr / g, respectively.

[0298] Following intravenous infusion of M-SPDB-3H-DM4 (12 mg / kg) to rabbits in Group 2, the concentration versus time profiles for each comeal layer had an apparent absorption phase, followed by a relatively stable concentration plateau. The comeal layer concentrations of radioactivity were lowest at 1 hour post-dose, but each layer had a mean Tmax value at a different time (endothelium, 24 hours; stroma, 168 hours; epithelium, 336 hours). Radioactivity was still quantifiable in all comeal layers throughout the duration of the study (336 hours post-dose). The mean Cmax concentrations of M-SPDB-3H-DM4-derived radioactivity in the comeal endothelium, comeal stroma, and comeal epithelium were 3,200 ± 2,510, 3,580 ± 451, and 9,370 ± 6,880 ng equivalents M-SPDB-3H-DM4 / g, respectively. The curve profiles did not afford the calculation of other pharmacokinetic parameters such as halflife or AUCo- / . The observed exposures (AUCo-t) of radioactivity in the comeal endothelium, comeal stroma, and comeal epithelium were 718,000, 940,000, and 1,490,000 ng equivalents M-SPDB-3H-DM4 hr / g, respectively. The mean comeal tissue to plasma concentration ratios started low and increased with time, ranging from 0.000432 to 1.61. Except for comeal epithelium at 336 hours, the ratios were generally below 0.5, indicating no preferential association or distribution of radioactivity to the cornea layers in Group 2.

[0299] Following intravenous infusion of M-SPDB-3H-DM4 (12 mg / kg) to rabbits in Group 2, dmg-derived radioactivity proceeded to distribute within the anterior tissues along the conventional outflow pathway including the aqueous humor, limbal sclera, and the remaining sclera. A concentration gradient was present from the cornea and ICB towards the tissues along aqueous humor outflow pathway. The mean radioactivity concentrations of anterior tissues generally peaked at 24 hours post-dose followed by a terminal elimination phase. Radioactivity was quantifiable through 336 hours post-dose. The Group 2 ti / 2 values which could be calculated were somewhat higher than the ti / 2 in blood and plasma, ranging from 128 to 158 hours. Even though these tissues had longer ti / 2, the exposures were much lower than more vascularized tissues. The tissue to plasma ratios for anterior ocular tissues increased over time, and no preferential distribution was observed for M-SPDB-3H-DM4.

[0300] Following intravenous infusion of M-SPDB-3H-DM4 (12 mg / kg) to rabbits in Group 2, dmg-derived radioactivity proceeded to distribute within the posterior tissues through the interior tissue layers of the eye including choroid-RPE, ICB, retina, optic nerve head, and optic nerve. Mean radioactivity concentrations generally peaked at 1 to 24 hours postdose and then displayed a distribution phase followed by a terminal elimination phase. The ti / 2 values which could be calculated were similar to the 11 / 2 in blood and plasma of approximately 100 hours, except for optic nerve (147 hours). Although the tissue to plasma ratios for posteriorocular tissues increased over time, no preferential distribution was observed for M-SPDB-3H- DM4.

[0301] Following intravenous infusion of M-SPDB-3H-DM4 at a dose level of 12 mg / kg to Group 2, there was more limited absorption and distribution of radioactivity into the structures of the eye as assessed by MARG. In the eyes obtained from Group 2 animals after an infusion of M-SPDB-3H-DM4, there was no discernible pattern of distribution or elimination. Regions that contained low levels of radioactivity included the iris and ciliary body at 1 and 24 hours, the choroid, sclera, and cornea at 96 hours, and the sclera at 168 hours. Other regions at all sampling times were at background levels.Summary Comparison of Groups 1 and 2

[0302] Single intravenous infusions at 12 mg / kg, M-sulfo-SPDB-3H-DM4 (IMGN853) and M-SPDB-3H-DM4 were well tolerated, and all animals appeared generally healthy and exhibited no overt signs of toxicity for the duration of the study. Although the animals appeared generally healthy, perilimbal comeal microcystic changes that often retained fluorescein stain in a multifocal punctate pattern were observed following administration of both test articles. However, this finding was more apparent and more frequent in animals administered M-SPDB-3H-DM4 as shown in the table below:Table B. Selected Ophthalmic ObservationsTest Article M-sulfo-SPDB- M-SPDB-3H-Formulation3H-DM4 DM4Ophthalmic Observation Group 1 2Study Day 5 perilimbal comeal microcystic changes Present 0 / 9 9 / 9 fluorescein staining multifocal punctate pattern over the microcystic lesions Present 0 / 9 8 / 9Study Day 8 perilimbal comeal microcystic changes Present 2 / 6 6 / 6 fluorescein staining multifocal punctate pattern over the microcystic lesions Present 2 / 6 3 / 6Study Day 15 perilimbal comeal microcystic changes Present 0 / 3 3 / 3 fluorescein staining multifocal punctate pattern over the microcystic lesions Present 2 / 3 3 / 3

[0303] No ocular abnormalities were noted in all nine Group 1 animals on Study Day 5. All nine animals in Group 2 had bilateral comeal microcystic changes in the perilimbal region. In all animals except for one, fluorescein stain was retained in a multifocal punctate pattern over the microcystic lesions. On Study Day 8, two of six animals in Group 1 had faint comeal microcystic lesions in both eyes and fluorescein stain retention in a multifocal punctate pattern over the microcystic lesions. All six animals in Group 2 had bilateral comeal microcystic lesions. Additionally, fluorescein stain was retained in five eyes of three animals. Although comeal microcysts were not visible in any of the three animals in Group 1 on Study Day 15, multifocal punctate fluorescein stain retention in the perilimbal region was observed in three eyes of two animals. This staining pattern was similar to that observed at other intervals. All three animals in Group 2 had bilateral comeal microcystic lesions (in two of three animals these microcystic changes were only faintly visible). Multifocal punctate fluorescein stain retention was observed in the perilimbal region of both eyes of all three animals.

[0304] Ratios of Group 2 to Group 1 mean blood and plasma pharmacokinetic parameters (Cmax and AUCo-t) were calculated for comparison, and these ratios show a difference of less than 2% between Group 1 and Group 2 mean Cmax values for blood and plasma. These ratios show Group 2 has 7 to 9% lower exposure values (AUCo-t) for blood and plasma compared to Group 1. See Figure 1.

[0305] Following intravenous infusion of M-sulfo-SPDB-3H-DM4 or M-SPDB-3H-DM4 (12 mg / kg) to rabbits, radioactivity in the peripheral ocular tissues (eyelid, bulbar conjunctiva, and nictitating membrane) generally displayed similar absorption / distribution kinetics for both groups. Calculated pharmacokinetic parameters for Groups 1 and 2 were very similar for the eyelids and bulbar conjunctiva. Although the nictitating membrane mean Cmax and Tmax values were similar between groups, Group 1 concentrations at 96 and 168 hours were higher, which factored into an observed exposure AUCo-t difference of approximately 20%.

[0306] Ratios of Group 2 to Group 1 mean pharmacokinetic parameters (Cmax and AUCo-t) were calculated for comparison for comeal layers. These ratios show a difference of less than 3% between Groups 1 and 2 comeal stroma values. Compared to Group 1, Group 2 has 30% lower and 13% lower Cmax and exposure values (AUCo-t) for comeal endothelium, respectively. Comeal epithelium ratios display a 3 - to 4-fold higher radioactivity concentration and exposure for Group 2 over Group 1, yielding comeal epithelium as the tissue with the largest difference between groups.

[0307] No preferential tissue distribution was observed for either test article, except for Group 2 comeal epithelium. Comeal epithelium displayed 3- to 4-fold higher radioactivityconcentration and exposure for Group 2 over Group 1, yielding corneal epithelium as the tissue with the largest difference between groups (Figure 2). These data indicate that following intravenous infusion of M-sulfo-SPDB-3H-DM4 (Group 1) or M-SPDB-3H-DM4 (Group 2), drug-derived radioactivity was widely distributed with elimination from ocular tissues similar to blood / plasma elimination.

[0308] Based on the levels of sensitivity and a low dose of radioactivity, there was limited ocular distribution of test substance-related radioactivity above background in all examined eyes when assessed by microautoradiography. Radioactivity was associated with most structures of the eye at 1 and 24 hours after administration of M-sulfo-SPDB-3H-DM4 in Group 1 and declined thereafter.

[0309] These data demonstrates that while exposure to M-sulfo-SPDB-3H-DM4 and M- SPDB-3H-DM4 was similar in the blood and most ocular tissues, exposure to M-SPDB-3H- DM4 was greater in the comeal epithelium and was associated with increased occurrence of microcysts.Example 2. Study of the Effects of Topical Ocular Treatments on AMC-Related Ocular Findings Following Weekly Intravenous Administration of M9346A-SPDB-DM4 to Male Dutch-Belted Rabbits

[0310] A purpose of this study was to evaluate the effects of topical ocular treatments on ocular findings related to an antibody-maytansinoid conjugate (AMC) following once weekly (up to two total doses) administrations of M9346A-SPDB-DM4 via intravenous (IV) slow bolus injection to male Dutch-Belted rabbits. Animals in Groups 2 through 6 were dosed via topical ocular instillation three or four times daily for at least 13 days (Cohort 2) or 5 (Cohort 1) weeks. M9346A-SPDB-DM4 was selected as the AMC for this study because it provides relatively consistent ocular toxicity. The dose level of 8. 1 mg / kg was selected to induce comeal keratopathy in most or all animals but not severe enough that any potential benefit of treatment with eye drops (topical ocular dose) would be unclear. Animals housed in a room with yellow light tested the hypothesis that comeal microcysts were at least partially induced by DM4 (and / or the linker payload or a metabolite) in the presence of light, as DM4 has previously been shown to be phototoxic in in vitro 3T3 neutral red uptake assays.

[0311] Male Dutch-Belted rabbits were assigned to nine groups, and doses were administered as indicated in the following tables for the first 8 groups. Animals were administered positive control article (M9346A-SPDB-DM4, also known as M-SPDB-DM4) via intravenous (IV) - (slow bolus) injection (for 1 to 2 minutes) at a volume of 1.5 mL / kg / dose(Groups 1 to 7) on Days 1 and 8 of the dosing phase (Cohorts 1 and 2) or at a volume of 2.22 mL / kg / dose (Group 8) once on Day 1 of the dosing phase (Cohorts 3 and 4). Animals in Groups 2 through 6 were administered 1 of 5 topical ocular instillation treatments: 0.0375 mg / eye / day Brimonidine (Brimonidine Tartrate Ophthalmic Solution 0.025%) (Group 2), 0.3 mg / eye / day Brimonidine (Brimonidine Tartrate Ophthalmic Solution 0.2%) (Group 3), 0.4 mg / eye / day Loteprednol (Loteprednol Etabonate Ophthalmic Suspension 0.2%) (Group 4), 2 mg / eye / day Prednisolone (Prednisolone Acetate Ophthalmic Suspension 1%) (Group 5), or 0.3 mg / eye / day Brimonidine 0.2% + 2 mg / eye / day Prednisolone (Group 6). Topical ocular drops were installed to the eyes at a volume of 50 pL / eye / dose three times daily (TID - 150 pL / eye / day for Groups 2, 3, and 6 [Brimonidine 0.2% only]) or four times daily (QID) - (200 pL / eye / day for Groups 4, 5, and 6 [Prednisolone only]). Positive control animals in Groups 7 and 8 were not administered topical ocular treatments, and Group 7 animals were housed under yellow light conditions during the light cycle. Three animals in Group 9 were not dosed.

[0312] Groups 2 and 3: Dose formulations (Brimonidine 0.025% [Group 2] or Brimonidine 0.2% [Group 3]) were administered topically TID (6 hours ± 30 minutes apart) on Days 1 through 13 (Cohort 2) or 1 through 35 (Cohort 1) of the dosing phase at a dose volume of 50 pL / eye / dose (150 pL / eye / day).

[0313] Groups 4 and 5: Dose formulations (Loteprednol [Group 4] or Prednisolone [Group 5]) were administered topically TID (3 hours ± 15 minutes apart) on Days 1 through 13 (Cohort 2) or 1 through 35 (Cohort 1) of the dosing phase at a dose volume of 50 pL / eye / dose.

[0314] Group 6: Dose formulations were administered topically on Days 1 through 13 (Cohort 2) or 1 through 35 (Cohort 1) of the dosing phase for Brimonidine 0.2% TID (6 hours ± 30 minutes apart) and Prednisolone QID (3 hours ± 15 minutes apart). When doses coincided, Brimonidine 0.2% was administered first, and Prednisolone was administered at least 5 minutes later. Dose times were based on the first animal / group dosed at the previous topical ocular dosing interval on that day, as applicable, at a dose volume of 50 pL / eye / dose for Brimonidine 0.2% and 50 pL / eye / dose for Prednisolone.

[0315] Day 1 of the dosing phase was defined as the first day of dosing for each cohort (Cohorts 1 through 4). Group 9 was not dosed. Day 1 of the dosing phase for animals in Group 9 (Cohort 5) was defined as the first day these animals were placed on study for necropsy collections. Dose Site C was designated as the left eye, and Dose Site B was designated as the right eye. Dosing involved restraining the head of the animal, gently opening the eyelid, and using a pipette to place the formulation directly on the cornea. After administration, the eye was allowed to close. Animals were not dosed while under the effects of anesthesia.

[0316] Assessment of toxicity was based on mortality, clinical observations, body weights, qualitative food consumption, ophthalmic observations, and anatomic pathology. Blood samples were collected for toxicokinetic evaluations. Additional sample collections included the following: tears for bioanalysis and eye tissues for exploratory immunohistochemistry. Corneal fluorescein staining was performed at the discretion of the examining Ophthalmologist.

[0317] No topical ocular treatment- or positive control article (M9346A-SPDB-DM4)- related mortality occurred. No topical ocular treatment- or positive control article-related clinical observations or alterations in qualitative food consumption, mean body weight, or mean body weight change were noted. No topical ocular treatment- or positive control article- related macroscopic observations were noted at unscheduled, interim, or terminal sacrifices.

[0318] During the dosing phase, findings (when present) were limited to multifocal punctate subepithelial comeal microcysts, which began in the perilimbal cornea and tended to migrate axially over time; sporadic instances of slight (1+) comeal fluorescein stain retention over microcysts; and comeal pigmentation. A review of the drawings of the extent of the microcysts and pigment demonstrated no clear and consistent differences between right and left eyes. Comeal pigmentation is commonly noted in pigmented rabbit strains and is thought to be a marker for limbal and comeal epithelial cell damage and conjunctivalization of the comeal epithelium. Microcysts were not observed in any group after Day 21.

[0319] Animals housed under white lighting conditions and administered 8.1 mg / kg M9346A-SPDB-DM4 (positive control article) via IV injection on Days 1 and 8 developed multifocal punctate subepithelial corneal microcysts starting on Day 7. This was followed by corneal pigmentation starting on Day 14 in animals administered only positive control article (no topical ocular treatments). Housing animals under yellow lighting conditions had no appreciable effect on comeal microcyst formation following administrations of 8. 1 mg / kg / dose M9346A-SPDB-DM4 on Days 1 and 14 with no topical ocular treatments. None of the topical ocular treatments were complete inhibitors of comeal microcyst formation, as all eyes in all groups eventually developed some degree of comeal microcyst formation by Day 14 or 17. However, compared with animals administered positive control only, animals administered 0.3 mg / eye / day Brimonidine 0.2% alone or in combination with 2 mg / eye / day Prednisolone had notably fewer eyes with comeal microcysts on Days 7 and 10 and a higher percentage of eyes with microcysts scored as few or faint on Days 7 through 17. Additionally, unlike animals administered positive control article only and the other dose groups, no eye administered 0.3 mg / eye / day Brimonidine 0.2% alone or in combination with Prednisolone developed comeal pigmentation. This suggested 0.3 mg / eye / day Brimonidine 0.2% had a more effective therapeutic effect on this tissue than the other treatment modalities. Topical corticosteroids (0.4 mg / eye / day Loteprednol or 2 mg / eye / day Prednisolone) did not appear to have meaningfully impacted the time to onset or frequency of comeal microcysts, compared with animals administered positive control article only. Collectively, this suggested the reductions in microcyst formation and subsequent pigmentation for animals administered Brimonidine combined with Prednisolone were attributable to 0.3 mg / eye / day Brimonidine 2% and not to the corticosteroid. Animals administered 0.0375 mg / eye / day Brimonidine 0.025% also had a reduced frequency of comeal microcyst formation on Day 7, but by Days 10 to 14, the frequency of comeal microcysts approximated that of animals administered positive control article only.

[0320] At one or more interim sacrifices, positive control article-related microscopic findings in the eyes of animals administered 12 mg / kg / dose M9346A-SPDB-DM4 alone were noted in the cornea and consisted of minimal or slight single cell epithelial necrosis and increased epithelial mitosis at >48 hours postdose, minimal to moderate atrophy of the epithelium at >120 hours postdose, minimal mononuclear cell infiltrate in the limbus of oneanimal at 96 hours postdose and of two animals at 144 hours postdose, and slight erosion / ulcer in one animal at 144 hours postdose and one animal at 168 hours postdose.

[0321] At the terminal sacrifice on Day 14, topical ocular administrations of 0.3 mg / eye / day Brimonidine 0.2% in combination with 2 mg / eye / day Prednisolone mitigated the positive control article-related microscopic findings, compared with animals administered positive control article only. Differences included an absence of mononuclear cell infiltrate at the limbus, erosion / ulcer of the cornea, and pigment in the comeal epithelium and a decreased incidence and severity of comeal epithelial atrophy. No definitive topical ocular treatment- related differences between topical ocular treatment and positive control animals were noted in the remaining groups at this sacrifice. No definitive topical ocular treatment-related impacts for the positive control article-related findings of single cell epithelial necrosis and increased epithelial mitosis in the cornea were noted for any topical ocular treatment group at the terminal sacrifice on Day 14, including those administered 0.3 mg / eye / day Brimonidine 0.2% in combination with 2 mg / eye / day Prednisolone.

[0322] At the terminal sacrifice on Day 36, topical ocular administrations of 0.3 mg / eye / day Brimonidine 0.2% alone or in combination with 2 mg / eye / day Prednisolone also mitigated the positive control article-related microscopic findings, compared with animals administered positive control article only. Differences included an absence of cornea epithelial atrophy, comeal erosion / ulcer, and pigment in the comeal epithelium and a decreased incidence / severity of mononuclear cell infiltrates at the limbus. No definitive topical ocular treatment-related differences were noted for the remaining groups.

[0323] The positive control article-related finding of single cell epithelial necrosis in the cornea at the interim sacrifices beginning on Day 2 and at the terminal sacrifice on Day 14 across groups was not observed in animals from any group at the terminal sacrifice on Day 36, including concurrent positive controls, suggesting the spontaneous resolution of the finding rather than a topical ocular treatment-related impact.

[0324] In summary, male Dutch-Belted rabbits were administered 12 mg / kg / dose M9346A-SPDB-DM4 (positive control article) only via IV administration once on Day 1 and were sacrificed at timed intervals between 24 and 168 hours postdose. Other male Dutch-Belted rabbits were administered 8.1 mg / kg / dose M9346A-SPDB-DM4 once via IV administration on Days 1 and 8 with topical ocular administrations of one of the following treatments TID or QID: 0.0375 mg / eye / day Brimonidine 0.025%, 0.3 mg / eye / day Brimonidine 0.2%, 0.4 mg / eye / day Loteprednol, 2 mg / eye / day Prednisolone, or 0.3 mg / eye / day Brimonidine 0.2% in combination with 2 mg / eye / day Prednisolone. For animals administered 12 mg / kg / doseM9346A-SPDB-DM4, the expected ophthalmic and microscopic findings were first noted on Day 3, indicating that the clinical presentation of comeal microcysts correlated with microscopic changes. Animals administered 8.1 mg / kg / dose M9346A-SPDB-DM4 developed the expected comeal microcysts by Day 7, and housing in white light or yellow light had no impact on microcyst development. Although none of the topical ocular treatments were complete inhibitors of comeal microcyst formation, administrations of 0.3 mg / eye / day Brimonidine 0.2% alone or in combination with 2 mg / eye / day Prednisolone mitigated the severity of ophthalmic and microscopic findings associated with the comeal microcysts that developed following administration of the positive control article.

[0325] As described in more detail below, clinical trials were conducted in human patients using dose levels and administration frequencies of eye drops that are consistent with those used in this study.Example 3. Vasoconstrictor Eye Drops Reduce Ocular Toxicity of IMGC936

[0326] A clinical study was conducted, wherein patients with relapsed or refractory, unresectable locally advanced or metastatic solid tumors were treated with intravenous IMGC936. The twenty-nine treated patients included 14 males and 15 females with a median age of 60 years. Of these patients, 13 had non-small cell lung cancer (NSCLC), 6 had triple negative breast cancer (TNBC), 8 had colorectal cancer (CRC), and 2 had pancreatic cancer. In addition to being treated with IMGC936, the patients also received eye drops as described in more detail below.

[0327] All patients were instmcted to use lubricating artificial tears. Patients were instmcted to start the regimen of lubricating artificial tears prior to each dose of IMGC936 and to continue application after dosing at least 4 times per day.

[0328] Some patients (n=15) were also instmcted to use brimonidine in addition to the lubricating eye drops. These patients were instmcted to use refrigerated, topical vasoconstricting eye drops (i.e., prescription strength brimonidine 0.1-0.2% twice daily, or potent adrenergic receptor agonist). Patients were instmcted that vasoconstricting eye drops should be applied within 1 hour prior to dosing of IMGC936 and continued throughout the study treatment.

[0329] Other patients (n=5) were instmcted to use corticosteroid eye drops in addition to the lubricating eye drops. These patients were instmcted to use corticosteroid eye drops 6 times daily on the day of IMGC936 dosing (Day 1) and through Day 4. Some of these patients were also instmcted to use corticosteroid eye drops 4 times daily on Days 5 to 8.

[0330] Patients receiving multiple drops were instructed to administer the drops at different times if feasible, i.e., to wait at least 15 to 30 minutes between the administration of different eye drops.

[0331] In total, 15 patients received brimonidine and lubricating eye drops; 5 patients received corticosteroid and lubricating eye drops; and 9 patients received only lubricating eye drops. Ocular adverse events were observed and compared in these patients. The results are shown in Table G below.Table G.1Treatment-emergent adverse events

[0332] These data demonstrate that patients treated with brimonidine + lubricant eye drops (15 patients) showed a delay of the first onset of keratopathy compared to the patients treated with corticosteroid + lubricant eye drops (median of 37 days vs 15 days). In addition, patientstreated with brimonidine + lubricant eye drops (15 patients) showed a delayed onset of keratopathy compared to patients that only received lubricant eye drops (9 patients) (median of 37 days vs 28 days).Example 4. Vasoconstrictor Eye Drops Reduce Ocular Toxicity of IMGN853

[0333] A clinical study is conducted, wherein patients with recurrent ovarian cancer with high FRa expression are treated with 6 mg / kg AIBW intravenous IMGN853 (mirvetuximab soravtansine) once every three-week cycle (Q3W). High FRa expression is defined as >75% cells exhibiting 2 or 3+ membrane staining intensity as measured by either the Ventana FOLR1 (FOLR1-2.1) CDX Assay or Ventana FOLR1 (FOLR1-2.1) RxDx Assay. The patients have received > 1 line of platinum-containing therapy and do not meet the criteria for primary platinum -refractory disease.

[0334] One hundred patients are randomized (1: 1) to 1 of 2 ocular adverse event (AE) risk mitigation strategy arms (primary prophylactic steroid eye drops versus primary prophylactic vasoconstricting eye drops). Randomization is stratified as follows: (1) platinum-resistant ovarian cancer (PROC) versus platinum-sensitive ovarian cancer (PSOC) and (2) baseline ocular surface findings versus no findings on ocular baseline examination. Baseline ophthalmic examination findings include ocular surface disorder consistent with dry eye syndrome, as indicated by reduced sodium fluorescein (NaFl) tear break-up time (< 10 seconds), or punctate epithelial erosion > Grade 1 by Oxford scale, versus no clinical finding of ocular surface disorder on baseline examination.

[0335] Patients in arm 1 (n=50) receive primary prophylactic steroid eye drops: prednisolone acetate ophthalmic suspension 1% 6 times daily on Days -1 (D-l) to D4 and 4 times daily (QID) on D5 to D8 of each cycle; lubricating eye drops 4 times daily (QID) throughout the entire cycle (doses follow steroid dosing, when given, by approximately 15 minutes); and 6 mg / kg AIBW IMGN853 Q3W on day 1 of each cycle.

[0336] Patients in arm 2 (n=50) receive primary prophylactic brimonidine tartrate ophthalmic solution eye drops 3 times daily (TID) on DI to D8 of each cycle, wherein vasoconstricting drops are started on the day of first infusion and begin before the first infusion on cycle 1 day 1 (C1D1); lubricating eye drops 4 times daily (QID) throughout the entire cycle (doses follow brimonidine dosing, when given, by approximately 15 minutes); and 6 mg / kg AIBW IMGN853 Q3W on day 1 of each cycle.

[0337] Prospective ophthalmic symptom assessments and examinations are performed on all patients. Ophthalmic examinations include slit lamp examination, manifest refraction, bestcorrected visual acuity (BCVA), and intraocular pressure (IOP) assessment at Baseline (< 14 days prior to Cycle 1 (Cl)), < 7 days prior to C2, C3, C5, and C7, as well as at the 30-Day Follow-up visit (± 14 days). Fundoscopy is additionally performed at least at Baseline and at the 30-Day Follow-up. Symptom assessments are performed at each cycle.

[0338] The incidence rate and severity are observed up to 18 weeks from Cycle 1 Day 1 (C1D1) or at the 30-Day Follow-up, whichever occurs first, of > Grade 2 IMGN853 -related corneal adverse events (AEs), in patients receiving IMGN853 who are asymptomatic (defined as ocular symptom assessment < Grade 1), in the 3-week period prior to the examination. The incidence rate and severity of IMGN853-related comeal AEs are assessed in all patients. The incidence rate and severity for asymptomatic patients is calculated as the proportion of patients who develop eligible IMGN853-related comeal AEs during the asymptomatic period. The asymptomatic period for each patient starts from the first dose of study dmg (C1D1) and ends with the onset of any ocular symptom (> Grade 2), last dose of study dmg + 30 days, start of a new anticancer therapy, or up to 18 weeks from C1D1, whichever occurs first. The incidence rate and severity of IMGN853-related comeal AEs among symptomatic patients is calculated similarly as the incidence rate and severity among asymptomatic patients, except the eligible person-time (symptomatic period) is defined differently. Symptomatic period starts from the onset of any ocular symptom (> Grade 2) and ends with the last dose of study dmg + 30 days, start of a new anticancer therapy, or up to 18 weeks from C1D1, whichever occurs first. Comparisons of the incidence rate and severity of IMGN853-related comeal AEs will be made between 1) asymptomatic (ocular symptom assessment < Grade 1) and symptomatic patients and 2) patients receiving corticosteroid versus vasoconstricting eye drop primary prophylaxis. The primary endpoint is the incidence rate and severity of IMGN853-related comeal AEs (> Grade 2) in asymptomatic patients (defined as ocular symptom assessment < Grade 1). A decreased incidence rate and severity in patients in arm 2 demonstrates that vasoconstrictors reduce ocular toxicity associated with IMGN853.Table 11. Grading of Comeal AEsTable 12. Grading for ocular symptoms. ADL = activities of daily living; ¥ Instrumental ADL: Ability to independently use a phone, do laundry, shop, prepare food, maintain housekeeping except occasional assistance, take own medications, and manage finances; € Self-care ADL: Ability to independently bathe, dress, transfer, eat, and perform personal toileting; * Per clinical practice and assessment of ophthalmologist or designee.Example 5. Vasoconstrictor Eye Drops Treat Ocular Toxicity of IMGN151

[0339] A clinical study is conducted, wherein patients with recurrent endometrial cancer or recurrent, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancers are treated with intravenous IMGN151.

[0340] Patients in arm 1 receive primary prophylactic steroid eye drops: prednisolone acetate ophthalmic suspension 1% 6 times daily on Days -1 (D-l) to D4 and 4 times daily (QID) on D5 to D8 of each cycle; preservative-free lubricating artificial tears starting from Cycle 1 Day 1 (C ID 1) prior to and after receiving IMGN 151 at least 4 times each day through study treatment (doses follow steroid dosing, when given, by approximately 15 minutes); and IMGN151 on day 1 of each cycle.

[0341] Patients in arm 2 (n=50) receive primary prophylactic brimonidine tartrate ophthalmic solution eye drops 3 times daily (TID) on DI to D8 of each cycle, wherein vasoconstricting drops are started on the day of first infusion and begin before the first infusion on cycle 1 day 1 (C1D1); preservative-free lubricating artificial tears starting from Cycle 1 Day1 (C1D1) prior to and after receiving IMGN151 at least 4 times each day through study treatment (doses follow brimonidine dosing, when given, by approximately 15 minutes); and IMGN151 on day 1 of each cycle.

[0342] If a patient develops corneal AEs of microcyst-like epithelial keratopathy > Grade2 (e.g., confluent keratopathy or keratopathy resulting in 3-line or more loss of BCVA), a prophylactic regimen of ocular vasoconstricting eye drops (brimonidine tartrate or equivalent adrenergic receptor agonist) is added for subsequent cycles. Vasoconstricting eye drops are self-administered 3 times daily throughout the cycle, starting the day prior to dosing in the subsequent cycle. Patients are instructed to wait > 15 minutes after brimonidine eye drop administration before instilling lubricating eye drops.

[0343] Patients’ ocular symptoms are monitored closely to demonstrate that the vasoconstricting eye drops reduce the severity of the ocular symptoms and / or prevent worsening of the ocular symptoms.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of administering an antibody maytansinoid conjugate (AMC) to a patient in need thereof comprising administering an effective amount of a vasoconstrictor and an effective amount of the AMC to the patient, wherein the vasoconstrictor is administered after the AMC is administered.

2. The method of claim 1, wherein the method reduces ocular toxicity.

3. The method of claim 1, wherein the method treats ocular toxicity.

4. A method of reducing ocular toxicity associated with the administration of an AMC to a patient, the method comprising administering an effective amount of a vasoconstrictor to the patient after the patient has been treated with the AMC.

5. A method of treating ocular toxicity associated with the administration of an AMC to a patient, the method comprising administering an effective amount of a vasoconstrictor to the patient after the patient has been treated with the AMC.

6. The method of claim 4 or 5, further comprising administering the AMC to the patient prior to administering the effective amount of the vasoconstrictor to the patient.

7. A method for safely and effectively treating of cancer in a patient, wherein the method comprises:(a) intravenously administering a therapeutically effective amount of an AMC to the patient; and(b) topically administering a vasoconstrictor to at least one eye of the patient after the administration of the AMC; wherein when the method is used to treat cancer in a population of patients the method results in a reduction in the frequency of one or more ocular toxicity compared to an identical comparator method practiced without the step of administering the vasoconstrictor.

8. A method for safely and effectively treating of cancer in a patient with an AMC delivered to the patient intravenously, wherein the method comprises: topically administering a vasoconstrictor to at least one eye of the patient after the administration of the AMC; wherein when the method is used to treat cancer in a population of patients the method results in a reduction in the frequency of one or more ocular toxicity compared to an identical comparator method practiced without the step of administering the vasoconstrictor.

9. The method of claim 7 or 8, wherein the comparator method comprises administering a steroid eye drop to at least one eye of the patient before the administration of the AMC.

10. The method of claim 9, wherein the steroid eye drop comprises prednisolone.

11. The method of any one of claims 7 to 10, wherein the method results in a reduction in the frequency of Grade 3 or higher ocular toxicity.

12. The method of any one of claims 7 to 10, wherein the method results in a reduction in the frequency of Grade 2 or higher ocular toxicity.

13. The method of any one of claims 7 to 12, wherein the reduction in frequency is an at least 10%, 20%, 30%, 40% or 50% reduction.

14. The method of any one of claims 7 to 12, wherein the frequency of the one or more ocular toxicity is reduced to less than 40%, 30% 20% or 10%.

15. An improved method for treating cancer in a patient by intravenous administration of an AMC to the patient, the improvement comprising reducing adverse eye toxicity by topically administering a vasoconstrictor to at least one eye of the patient after the administration of the AMC.

16. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least two days after administration of the AMC, optionally where the at least two days are the two consecutive days after the administration of the vasoconstrictor.

17. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least three days after administration of the AMC, optionally where the at least three days are the three consecutive days after the administration of the vasoconstrictor.

18. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least four days after administration of the AMC, optionally where the at least four days are the four consecutive days after the administration of the vasoconstrictor.

19. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least five days after administration of the AMC, optionally where the at least five days are the five consecutive days after the administration of the vasoconstrictor.

20. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least six days after administration of the AMC, optionally where the at least six days are the six consecutive days after the administration of the vasoconstrictor.

21. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least seven days after administration of the AMC, optionally where the at least seven days are the seven consecutive days after the administration of the vasoconstrictor.

22. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least eight days after administration of the AMC, optionally where the at least eight days are the eight consecutive days after the administration of the vasoconstrictor.

23. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least fourteen days after administration of the AMC, optionally where the at least fourteen days are the fourteen consecutive days after the administration of the vasoconstrictor.

24. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least twenty-one days after administration of the AMC, optionally where the at least twenty-one days are the twenty-one consecutive days after the administration of the vasoconstrictor.

25. The method of any one of claims 1-15, wherein the vasoconstrictor is administered on at least twenty-eight days after administration of the AMC, optionally where the atleast twenty-eight days are the twenty-eight consecutive days after the administration of the vasoconstrictor.

26. The method of any one of claims 1-25, wherein the AMC is administered once every three weeks.

27. The method of claim 26, wherein the vasoconstrictor is administered at least once a day throughout the three weeks.

28. The method of claim 26, wherein the vasoconstrictor is administered on the seven consecutive days after the administration of the vasoconstrictor, but is not administered on the following fourteen days.

29. The method of claim 26, wherein the vasoconstrictor is administered on the fourteen consecutive days after the administration of the vasoconstrictor, but is not administered on the following seven days.

30. The method of any one of claims 1-25, wherein the AMC is administered once every four weeks.

31. The method of claim 30, wherein the vasoconstrictor is administered at least once a day throughout the four weeks.

32. The method of claim 30, wherein the vasoconstrictor is administered on the seven consecutive days after the administration of the vasoconstrictor, but is not administered on the following twenty-one days.

33. The method of claim 30, wherein the vasoconstrictor is administered on the fourteen consecutive days after the administration of the vasoconstrictor, but is not administered on the following fourteen days.

34. The method of claim 30, wherein the vasoconstrictor is administered on the twenty- one consecutive days after the administration of the vasoconstrictor, but is not administered on the following seven days.

35. The method of any one of claims 1-34, wherein the vasoconstrictor is also administered prior to administration of the AMC, and / or at the same time as administration of the AMC.

36. The method of any one of claims 1-35, wherein the vasoconstrictor is also administered immediately prior to the administration of the AMC.

37. The method of any one of claims 1-36, wherein the vasoconstrictor is administered immediately after the administration of the AMC.

38. The method of any one of claims 1-37, wherein the vasoconstrictor is administered three times per day.

39. The method of any one of claims 1-37, wherein the vasoconstrictor is administered twice per day.

40. The method of any one of claims 1-37, wherein the vasoconstrictor is administered once daily.

41. The method of any one of claims 1-37, wherein the vasoconstrictor is administered four times per day.

42. The method of any one of claims 1-37, wherein the vasoconstrictor is administered once per day to five times per day.

43. The method of any one of claims 1-42, wherein the vasoconstrictor is administered as an eye drop, optionally wherein the eye drop is refrigerated.

44. The method of any one of claims 1-43, wherein the vasoconstrictor is selected from the group consisting of brimonidine, apraclonidine, dipivefrin, epinephrine, naphazoline, phenylephrine, oxymetazoline, tetryzoline, and combinations thereof.

45. The method of any of claims 1-44, wherein the vasoconstrictor is an alpha-2 adrenergic receptor agonist.

46. The method of any one of claims 1-45, wherein the vasoconstrictor is brimonidine.

47. The method of claim 46, wherein the vasoconstrictor is brimonidine tartrate.

48. The method of claim 47, wherein the vasoconstrictor is brimonidine tartrate 0. 1-0.2%.

49. The method of claim 48, wherein the vasoconstrictor comprises 0.2% w / v brominidine tartrate.

50. The method of claim 48, wherein the vasoconstrictor comprises 0.15% w / v brominidine tartrate.

51. The method of claim 48, wherein the vasoconstrictor comprises 0.1% w / v brominidine tartrate.

52. The method of any one of claims 2-51, wherein the ocular toxicity is Grade 2 or higher ocular toxicity.

53. The method of any one of claims 2-51, wherein the ocular toxicity is Grade 3 or higher ocular toxicity.

54. The method of any one of claims 2-53, wherein the ocular toxicity is dry eye, blurred vision, corneal keratopathy, comeal microcysts, comeal edema, and / or comeal haze.

55. The method of any one of claims 2-53, wherein the ocular toxicity is a comeal condition or disorder.

56. The method of claim 55, wherein the comeal condition or disorder is punctate keratitis, confluent keratitis, keratopathy, confluent keratopathy, cornea epithelial defect, comeal ulcer, cornea stromal opacity, comeal perforation, or any combination thereof.

57. The method of any one of claims 2-56, wherein the ocular toxicity does not comprise cornea stromal opacity or cornea subepithelial opacity.

58. The method of any one of claims 1-57, wherein the maytansinoid is DM1.

59. The method of any one of claims 1-57, wherein the maytansinoid is DM4.

60. The method of any one of claims 1-57, wherein the maytansinoid is DM21.

61. The method of any one of claims 1-60, wherein the AMC comprises an antibody or antigen-binding fragment thereof that binds to FRa.

62. The method of claim 61, wherein the antibody or antigen-binding fragment thereof that binds to FRa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24 and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO:27.

63. The method of claim 61, wherein the antibody or antigen-binding fragment thereof that binds to FRa is a biparatopic antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24, a light chain variable region comprising the amino acid sequence of SEQ ID NO:27, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:26.

64. The method of any one of claims 1-60, wherein the AMC comprises an antibody or antigen-binding fragment thereof that binds to ADAM9.

65. The method of claim 64 wherein the antibody or antigen-binding fragment thereof that binds to ADAM9 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO:28.

66. The method of any one of claims 1-65, wherein the AMC comprises an IgG antibody or antigen-binding fragment.

67. The method of any one of claims 1-66, wherein the AMC comprises an IgGl antibody or antigen-binding fragment.

68. The method of any one of claims 1-67, wherein the AMC comprises an antibody comprising a human IgGl constant region.

69. The method of any one of claims 1-68, wherein the AMC comprises an antibody or antigen-binding fragment thereof linked to a maytansinoid through the s-amino group of a lysine residue of the antibody or antigen-binding fragment thereof.

70. The method of any one of claims 1-68, wherein the AMC comprises an antibody or antigen-binding fragment thereof is linked to the maytansinoid through a Cys thiol group.

71. The method of any one of claims 1-57, wherein the AMC is IMGN853.

72. The method of any one of claims 1-57, wherein the AMC is IMGN151.

73. The method of any one of claims 1-57, wherein the AMC is IMGC936.

74. The method of any one of claims 1-73, wherein the patient has cancer.

75. The method of claim 74, wherein the cancer is ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, lung cancer, breast cancer, gastroesophageal cancer, colorectal cancer, or pancreatic cancer.

76. The method of claim 74, wherein the ovarian cancer is epithelial ovarian cancer.

77. The method of claim 74, wherein the peritoneal cancer is primary peritoneal cancer.

78. The method of claim 74, wherein the lung cancer is non-squamous non-small cell lung cancer.

79. The method of claim 74, wherein the breast cancer is triple negative breast cancer.

80. The method of any one of claims 1-57, wherein the AMC is IMGN853 and the patient has recurrent epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

81. The method of claim 80, wherein the patient has FRa positive platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, and wherein the patient has received one to three prior systemic treatment regimens.

82. The method of claim 80 or 81, wherein IMGN853 is administered at a dose of 6 mg / kg adjusted ideal body weight on day 1 of a three week cycle and brimonidine tartrate is administered three times daily on day 1 to day 8 of the cycle.

83. The method of claim 80 or 81, wherein IMGN853 is administered at a dose of 6 mg / kg adjusted ideal body weight on day 1 of a three week cycle and brimonidine tartrate is administered three times daily on day 1 to day 8 of the cycle, and wherein brimonidine tartrate is administered on day 1 before the administration of IMGN853.

84. The method of any one of claims 1-57, wherein the AMC is IMGN151 and the patient has recurrent endometrial cancer, recurrent high-grade serous epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer.

85. The method of claim 84, wherein the patient has FRa positive platinum -resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, and wherein the patient has received one to three prior systemic treatment regimens.

86. The method of any one of claims 1-57, wherein the AMC is IMGC936 and the patient has non-squamous non-small cell lung cancer, triple -negative breast cancer, gastroesophageal cancer, colorectal cancer, or pancreatic cancer.

87. The method of any one of claims 1-86, wherein the method further comprises administering a steroid eye drop to the patient.

88. The method of claim 87, wherein the steroid is prednisolone.

89. The method of any one of claims 1-88, wherein the method further comprises administering a corticosteroid eye drop to the patient.

90. The method of any one of claims 1-89, further comprising administering lubricating eye drops to the patient.

91. The method of claim 90, wherein the lubricating eye drops are administered after the vasoconstrictor.

92. The method of claim 91, wherein the lubricating eye drops are administered about 5 minutes to about an hour after the administration of the vasoconstrictor.

93. The method of claim 92, wherein the lubricating eye drops are administered about 10 minutes to about 30 minutes after the administration of the vasoconstrictor.

94. The method of claim 93, wherein the lubricating eye drops are administered about 15 minutes after the administration of the vasoconstrictor.

95. The method of any one of claims 90-94, wherein the lubricating eye drops are administered four times a day.

96. The method of any one of claims 90-95, wherein the lubricating eye drops are administered on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 28 days after administration of the AMC.

97. The method of any one of claims 90-95, wherein the lubricating eye drops are administered on every day of the treatment cycle.

98. The method of any one of claims 1-97, wherein the patient has ocular symptoms prior to the administration of the vasoconstrictor.

99. The method of claim 98, wherein the ocular symptoms comprise comeal microsyst- like epithelial keratopathy > Grade 2.

100. The method of any one of claims 1-97, wherein the patient does not have ocular symptoms prior to the administration of the vasoconstrictor.

101. The method of claim 100, wherein the patient is at risk of developing ocular symptoms.

102. The method of any one of claims 1-101, wherein the patient is a human patient.

103. Use of a vasoconstrictor in the manufacture of a medicament for use in the method of any one of claims 1-102.

104. Use of an AMC in the manufacture of a medicament for use in the method of any one of claims 1-102.

105. Use of a vasoconstrictor in the manufacture of a medicament substantially as described herein.

106. Use of an AMC in the manufacture of a medicament for use in a method substantially as described herein.

107. A method substantially as described herein.

108. A composition for the treatment of a condition substantially as described herein.

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