Humanized Anti-CD40 antibodies for treating sjÖgren's disease

Abstract

The present disclosure relates to dosing regimens of pharmaceutical compositions of anti- CD40 antibodies, such as humanized anti-CD40 antibodies, and uses thereof in the treatment of Sjögren's disease.

Description

[0001] HUMANIZED ANTI-CD40 ANTIBODIES FOR TREATING SJOGREN’S DISEASE

[0002] Sequence Listing

[0003] This application contains a Sequence Listing which has been filed electronically in Extensible Markup Language (XML) format and is hereby incorporated by reference in its entirety. Said XML copy, created on March 27, 2025, is named 51383-010WO2_Sequence_Listing_3_27_25.XML and is 20,936 bytes in size.

[0004] Background

[0005] Suppression of the immune system, particularly the humoral immune system, is beneficial in treatment of autoimmune disorders, such as Sjogren’s disease. One target for suppressing the immune system is the CD40 / CD154 interaction. CD40 is expressed primarily on the surface of B lymphocytes and other antigen-presenting cells (APCs) such as dendritic cells and macrophages. CD154 is expressed primarily on the surface of T cells. The interaction between these two proteins is associated with B cell activation, which triggers cytokine expression as well as expression of cell surface markers including CD23, CD80, and CD86. Antibodies (e.g., humanized antibodies) that target the CD40 / CD154 interaction have been developed. There exists a need for therapeutic regimens that are effective for treating Sjogren’s disease.

[0006] Summary

[0007] In one aspect, disclosed is a method of treating Sjogren’s disease in a subject in need thereof by administering (e.g., intravenously, subcutaneously, or intrathecally) to the subject a pharmaceutical composition containing a humanized anti-CD40 antibody or antigen-binding fragment thereof with a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 9 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.

[0008] In a second aspect, disclosed is a method of immunosuppression in a human subject with Sjogren’s disease. The method includes administering (e.g., intravenously, subcutaneously, or intrathecally) to the subject a pharmaceutical composition containing a humanized anti-CD40 antibody or antigen-binding fragment thereof with a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 9 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.

[0009] The antibody or antigen-binding fragment thereof may be administered at a dosage of about 50 mg to about 1000 mg. For example, the antibody or antigen binding fragment thereof may be administered at a dosage of about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 100 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 200 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 300 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 400 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 500 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 600 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 700 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 800 mg. The antibody or antigen-binding fragment thereof may be administered about once per week, once every two weeks, once every three weeks, or once every four weeks. The subject may be treated by administration (e.g., subcutaneously) of 400 mg about once per week (e.g., once every 7 days), once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 400 mg once per week. In some embodiments, the method includes administration (e.g., subcutaneously) of 400 mg once every two weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 400 mg once every four weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 500 mg once per week. In some embodiments, the method includes administration (e.g., subcutaneously) of 500 mg once every two weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 500 mg once every four weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 600 mg once per week. In some embodiments, the method includes administration (e.g., subcutaneously) of 600 once every two weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 600 mg once every four weeks.

[0010] In some embodiments, the antibody or antigen-binding fragment thereof is administered (e.g., subcutaneously, intravenously, or intrathecally) at a dosage of about 1 mg / kg to about 20 mg / kg (e.g., about 5 mg / kg to about 20 mg / kg, e.g., about 5 mg / kg to about 10 mg / kg, e.g., about 5.5 mg / kg to about 8.5 mg / kg, e.g., about 6 mg / kg to about 8 mg / kg, e.g., about 6.5 mg / kg to about 7.5 mg / kg, e.g., about 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, 16.5 mg / kg, 17 mg / kg, 17.5 mg / kg, 18 mg / kg, 18.5 mg / kg, 19 mg / kg, 19.5 mg / kg, or 20 mg / kg).

[0011] In some embodiments, the method includes administering (e.g., subcutaneously, intravenously, or intrathecally) a loading dose (e.g., an initial dose at the onset of treatment) of about 100 mg to about 1 ,000 mg (e.g., about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1 ,000 mg, e.g., about 400 mg, 600 mg, or 800 mg). In some embodiments, the method includes administering (e.g., subcutaneously, intravenously, or intrathecally) one or more maintenance doses of about 50 mg to 1000 mg (e.g., 400 mg), e.g., about once per week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the loading dose is about 600 mg or about 800 mg. The loading dose may be administered in two injections (e.g., two subcutaneous injections, e.g., two doses of about 300 mg each or two doses of about 400 mg each). In some embodiments, the loading dose (e.g., subcutaneously) is 800 mg, and the method includes once weekly administration of 400 mg (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 800 mg, and the method includes administration of 400 mg once every two weeks (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 800 mg, and the method includes administration of 400 mg once every four weeks (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 1000 mg, and the method includes once weekly administration of 400 mg (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 1000 mg, and the method includes administration of 400 mg once every two weeks (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 1000 mg, and the method includes administration of 400 mg once every four weeks (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 1000 mg, and the method includes administration of 500 mg once per week (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 1000 mg, and the method includes administration of 500 mg once every two weeks (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 1000 mg, and the method includes administration of 500 mg once every four weeks (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 1000 mg, and the method includes administration of 600 mg once per week (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 1000 mg, and the method includes administration of 600 mg once every two weeks (e.g., subcutaneously). In some embodiments, the loading dose (e.g., subcutaneously) is 1000 mg, and the method includes administration of 600 mg once every four weeks (e.g., subcutaneously). In some embodiments, the method includes administration (e.g., subcutaneously) of 400 mg once per week without a loading dose. In some embodiments, the method includes administration (e.g., subcutaneously) of 400 mg once every two weeks without a loading dose. In some embodiments, the method includes administration (e.g., subcutaneously) of 400 mg once every four weeks without a loading dose. In some embodiments, the method includes administration (e.g., subcutaneously) of 500 mg once per week without a loading dose. In some embodiments, the method includes administration (e.g., subcutaneously) of 500 mg once every two weeks without a loading dose. In some embodiments, the method includes administration (e.g., subcutaneously) of 500 mg once every four weeks without a loading dose. In some embodiments, the method includes administration (e.g., subcutaneously) of 600 mg once per week without a loading dose. In some embodiments, the method includes administration (e.g., subcutaneously) of 600 mg once every two weeks without a loading dose. In some embodiments, the method includes administration (e.g., subcutaneously) of 600 mg once every four weeks without a loading dose. In some embodiments, the loading dose is administered at a dosage of about 1 mg / kg to about 20 mg / kg (e.g., about 5 mg / kg to about 20 mg / kg, e.g., about 5 mg / kg to about 10 mg / kg, e.g., about 11 .5 to about 14.5 mg / kg, e.g., about 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, 16.5 mg / kg, 17 mg / kg, 17.5 mg / kg, 18 mg / kg, 18.5 mg / kg, 19 mg / kg, 19.5 mg / kg, or 20 mg / kg).

[0012] In some embodiments, one or more maintenance doses of the anti-CD40 antibody or antigenbinding fragment thereof are administered (e.g., subcutaneously, intravenously, or intrathecally) to the subject. In some embodiments, the method includes administering (e.g., subcutaneously, intravenously, or intrathecally) a maintenance dose of about 50 mg to about 1 ,000 mg (e.g., 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg). In some embodiments, the maintenance dose is administered at a dosage of about 1 mg / kg to about 20 mg / kg (e.g., about 5 mg / kg to about 20 mg / kg, e.g., about 5 mg / kg to about 10 mg / kg, e.g., about 5.5 mg / kg to about 8.5 mg / kg, e.g., about 6 mg / kg to about 8 mg / kg, e.g., about 6.5 mg / kg to about 7.5 mg / kg, e.g., about 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5. mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, 16.5 mg / kg, 17 mg / kg, 17.5 mg / kg, 18 mg / kg, 18.5 mg / kg, 19 mg / kg, 19.5 mg / kg, or 20 mg / kg). In some embodiments, the loading dose is administered intravenously or intrathecally at a dosage of about 5 mg / kg to about 20 mg / kg of the antibody or antigen-binding fragment thereof.

[0013] In some embodiments, the maintenance dose is provided to maintain a desired minimum blood, plasma, or serum concentration of the antibody or antigen-binding fragment thereof. For example, in some embodiments, it is desirable to maintain a minimum concentration (e.g., a trough concentration) of at least about 2 pg / mL, 5 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, 25 pg / mL (e.g., at least 30 pg / mL, 40 pg / mL, 50 pg / mL, 60 pg / mL, 70 pg / mL, 80 pg / mL, 90 pg / mL, 100 pg / mL, 110 pg / mL, 120 pg / mL, 130 pg / mL, 140 pg / mL, 150 pg / mL, 160 pg / mL, 170 pg / mL, 180 pg / mL, 190 pg / mL, 200 pg / mL, 210 pg / mL, 220 pg / mL, 230 pg / mL, 240 pg / mL, or 250 pg / mL, 260 pg / mL, 270 pg / mL, 280 pg / mL, 290 pg / mL, 300 pg / mL (e.g., a range from about 2 pg / mL to about 5 pg / mL; from about 2 pg / mL to about 10 pg / mL; from about 2 pg / mL to about 20 pg / mL; from 5 pg / mL to about 20 pg / mL; from about 10 pg / mL to about 20 pg / mL; or from about 10 pg / mL to about 50 pg / mL) of the antibody or antigen-binding fragment thereof in the blood, plasma, or serum of the subject. The method may include administering a maintenance dose of 50 mg to 1 ,000 mg (e.g., 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg, e.g., at a dosage of about 200 mg or 400 mg) of the antibody or antigen-binding fragment thereof. In some embodiments, the maintenance dose is administered at a dosage of about 1 mg / kg to about 20 mg / kg (e.g., about 5 mg / kg to about 20 mg / kg, e.g., 5 mg / kg to about 10 mg / kg, e.g., about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 1 1 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg). In some embodiments, the loading dose is administered intravenously or intrathecally at a dosage of about 5 mg / kg to about 20 mg / kg of the antibody or antigen-binding fragment thereof.

[0014] The maintenance dose(s) can be repeatedly administered, e.g., once every week, once every two weeks, once every three weeks, or once every four weeks, or as needed. The maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject). The timing of administration of the maintenance dose and / or the timing between maintenance doses may be selected based on the PK profile of the antibody or antigen-binding fragment thereof in, e.g., the blood, plasma, or serum of the subject.

[0015] In some embodiments, the pharmaceutical composition administered to the subject includes a concentration of the antibody or antigen-binding fragment thereof from about 100 mg / mL to about 300 mg / mL and, optionally, in a volume of about 0.5 to 5.0 mL (e.g., 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1 .0 mL, 1.1 mL, 1 .2 mL, 1 .3 mL, 1 .4 mL, 1 .5 mL, 1 .6 mL, 1 .7 mL, 1 .8 mL, 1 .9 mL, 2.0 mL, 3.0 mL, 4.0 mL, or 5.0 mL, e.g., about 1 .0 to 2.0 mL). In some embodiments, the antibody or antigen-binding fragment thereof is administered at a concentration of about 200 mg / mL.

[0016] In some embodiments, the antibody or antigen-binding fragment thereof is present in the pharmaceutical composition at a concentration of from about 100 mg / mL to about 300 mg / mL (e.g., 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, or 300 mg / mL, e.g., about 200 mg / mL.

[0017] In some embodiments, the pharmaceutical composition includes, in addition to the antibody or antigen-binding fragment thereof (e.g., in a concentration of about 100-300 mg / mL and, optionally, in a volume of about 0.5 mL-3.0 mL), sodium acetate, arginine, glutamate, polysorbate 20. For example, the pharmaceutical composition includes sodium acetate in an amount of from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, such as, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM); arginine in an amount of from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, such as, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM); glutamate in an amount of from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, such as, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM); and polysorbate 20 in an amount of from about 0.001 % (w / v) to about 0.1 % (w / v) (e.g., about 0.002% (w / v), 0.003% (w / v), 0.004% (w / v), 0.005% (w / v), 0.006% (w / v), 0.007% (w / v), 0.008% (w / v), 0.009% (w / v), 0.01 % (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v), or 0.1 % (w / v)). The pharmaceutical composition may have a pH of about 5.0 to 6.0, such as a pH of 5.4.

[0018] In some embodiments, the pharmaceutical composition includes polysorbate 20, acetate, and one or more polar excipients. The polar excipient may be or may include, for example, a sugar, a polyol, or an amino acid. In some embodiments, the sugar is, for example, sucrose, trehalose, fructose, lactose, dextrose, or mannitol. In some embodiments, the polyol is, for example, polyethylene glycol or sorbitol. In some embodiments, the amino acid is one or more of alanine, arginine, aspartic acid, asparagine, carnitine, citrulline, ornithine, glycine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine. The acetate may include, for example, sodium acetate (e.g., in salt form) or acetate in its ionic form.

[0019] In some embodiments, the pharmaceutical composition includes from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 45 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) acetate.

[0020] In some embodiments, the pharmaceutical composition includes from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM) of the polar excipient. In some embodiments, the pharmaceutical composition includes about 50 mM of the polar excipient.

[0021] In some embodiments, the pharmaceutical composition includes about 100 mM of the polar excipient.

[0022] In some embodiments, the pharmaceutical composition includes about 150 mM of the polar excipient.

[0023] In some embodiments, the pharmaceutical composition includes about 200 mM of the polar excipient.

[0024] In some embodiments, the pharmaceutical composition includes from about 1 % (w / v) to about 10% (w / v) (e.g., about 2% (w / v) to about 8% (w / v), e.g., about 1 % (w / v), 1 .5 % (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v), 5% (w / v), 5.5% (w / v), 6% (w / v), 6.5% (w / v), 7% (w / v), 7.5% (w / v), 8% (w / v), 8.5% (w / v), 9% (w / v), 9.5% (w / v), 10% (w / v)) of the polar excipient. In some embodiments, the pharmaceutical composition includes about 2.5% (w / v) of the polar excipient. In some embodiments, the pharmaceutical composition includes about 7% (w / v) of the polar excipient.

[0025] In some embodiments, the pharmaceutical composition includes from about 0.001 % (w / v) to about 0.1 % (w / v) (e.g., about 0.005% (w / v) to 0.05% (w / v), e.g., about 0.001 % (w / v), 0.002% (w / v), 0.003% (w / v), 0.004% (w / v), 0.005% (w / v), 0.006% (w / v), 0.007% (w / v), 0.008% (w / v), 0.009% (w / v), 0.01 % (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v), or 0.1 % (w / v)) polysorbate 20.

[0026] The composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g., about 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0, e.g., about 5.4.

[0027] In some embodiments, the composition is administered (e.g., subcutaneously) at a dosage of about 1 mg / kg, 1 .5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg.

[0028] The composition may be administered, e.g., once per day, once per week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the composition is administered during a treatment regimen of at least one day, one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, one year, or longer, such as for the life of the subject. In one embodiment, the composition is administered to the subject until clinical remission is achieved or a minimum low disease activity is achieved.

[0029] The composition may be administered during a treatment regimen of about 12 weeks, 24 weeks, 26 weeks, 48 weeks, 52 weeks, 96 weeks, 104 weeks, or longer (e.g., for six months, one year, two years, three years, four years, five years, six years, or more, such as for the life of the subject). In one embodiment, the composition is administered to the subject until clinical remission or a reduction (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) in sequelae associated with the Sjogren’s disease, such as dry eyes or dry mouth, is achieved or a minimum low disease activity is achieved. The method may be administered until one or more symptoms of the Sjogren’s disease improve.

[0030] One or more efficacy metrics can demonstrate efficacy of treatment. The efficacy metric may include a EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score that decreases by at least 3 following administration of the composition. The efficacy metric may include an ESSDAI score less than 5 following administration of the composition. The efficacy metric may include an improvement in ESSDAI score following administration of the composition. The efficacy metric may include a Sjogren's Tool for Assessing Response (STAR) score > 5 following administration of the composition. The efficacy metric may include improvement, following administration of the composition, in one of more of the individual STAR domains selected from the group consisting of systemic activity assessed by ESSDAI score, patient-reported outcome assessed by ESSPRI score, lacrimal gland function assessed by Schirmer’s test score, salivary gland function, and biological function assessed by IgG decrease of at least 10% or rheumatoid factor (RF) level decrease of at least 25%. For example, the efficacy metric may include IgG decrease of at least 10% or rheumatoid factor (RF) level decrease of at least 25% following administration of the composition. The efficacy metric may include an increase of at least 25% in unstimulated salivary flow following administration of the composition or, alternatively, an increase in unstimulated salivary flow following administration of the composition if no saliva was produced prior to administration of the composition. The efficacy metric may include an improvement in stimulated salivary flow following administration of the composition. The efficacy metric may include a Schrimer’s test score of 10 mm or higher following administration of the composition. The efficacy metric may include an increase of 5 mm or more in Schrimer’s test score following administration of the composition if Schrimer’s test score was below 5 mm prior to administration of the composition or, alternatively, Schirmer’s test score > 5 mm following administration of the composition if Schrimer’s test score is 10 mm or higher prior to administration of the composition. The efficacy metric may include a decrease in a EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) score of at least 1 or at least 15% following administration of the composition. The efficacy metric may include an improvement in a EuroQol 5 Dimension 5 Level

[0031] (EQ-5D-5L) score following administration of the composition. The efficacy metric may include an increase in a Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) score following administration of the composition. The efficacy metric may include an Evaluator

[0032] Global Assessment (EGA) score of 3 or less following administration of the composition. The efficacy metric may include an EGA score of 2 or less following administration of the composition. The efficacy metric may include an EGA score of 1 following administration of the composition. The efficacy metric may include an improvement in EGA score following administration of the composition.

[0033] The efficacy metric may include an Evaluator Global Assessment of Change (EGAC) score of 0 to 2 following administration of the composition. The efficacy metric may include an EGAC score of 0 to 1 following administration of the composition. The efficacy metric may include an EGAC score of 0 following administration of the composition. The efficacy metric may include a Patient Global

[0034] Impression of Severity (PGIS) score of 3 or less following administration of the composition. The efficacy metric may include a PGIS score of 2 or less following administration of the composition. The efficacy metric may include a PGIS score of 1 following administration of the composition. The efficacy metric may include a Patient Global Impression of Change (PGIC) score of 0 to 2 following administration of the composition. The efficacy metric may include a PGIC score of 0 to 1 following administration of the composition. The efficacy metric may include a PGIC score of 0 following administration of the composition.

[0035] In some embodiments, the method inhibits or reduces (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) one or more sequelae associated with Sjogren’s disease. The one or more symptoms associated with Sjogren’s disease may include, for example, dry mouth, dry eyes, pain, fatigue, dry skin, vaginal dryness, chronic cough, or numbness (e.g., in the arms or legs). In some embodiments, the inhibition or reduction of symptoms or sequelae of Sjogren’s disease is measured with respect to a control (e.g., relative to the subject prior to treatment). In some embodiments, a control is indicative of the one or more symptoms of Sjogren’s disease in the subject before the treatment (also referred to as a baseline). In some embodiments, the control is indicative of the one or more symptoms of Sjogren’s disease as determined by evaluating health information from Sjogren’s disease patients overtime, demonstrating the natural progress of the condition, which can be obtained, for example, from a natural history study of Sjogren’s disease. In some embodiments, a control is indicative of the one or more symptoms of Sjogren’s disease in a control subject with the same disease status without treatment. In some embodiments, a control is indicative of the one or more symptoms of Sjogren’s disease in a subject with the same disease status, who is treated with a placebo. In some embodiments, a control is indicative of a disease state in a subject having the disease, who receives a standard of care therapy in absence of administration of a humanized anti-CD40 antibody or antigen-binding fragment thereof. The reduction may include a reduction in frequency and / or intensity of symptoms.

[0036] In some embodiments, the method improves, stabilizes or reduces one or more symptoms of Sjogren’s disease in the subject relative to a control. In some embodiments, the subject is 18 to 81 years of age. In some embodiments, the subject is > 18 and < 81 years of age. In some embodiments, the subject is 18 years or age or older. In some embodiments, the subject has a diagnosis of Sjogren’s disease according to 2016 ACR- EULAR Classification Criteria. In some embodiments, the subject has an ESSDAI score > 5. In some embodiments, the subject has an ESSDAI score > 5 counting only the biological, hematological, articular, cutaneous, glandular, lymphadenopathy, and constitutional organ domains. In some embodiments, the subject is seropositive for anti-Sjogren’s syndrome antibodies. In some embodiments, the subject has a stimulated whole salivary flow rate of > 0.1 mL / min.

[0037] Definitions

[0038] As used herein, the term “about” means ±10% of the recited value.

[0039] Brief Description of the Drawings

[0040] FIG. 1 is a schematic drawing showing the KPL-404 clinical trial scheme. Patients randomized to KPL-404 groups in Part A will continue the same treatment assignment in Part B (without unblinding to prior treatment assignment). Patients randomized to Placebo in Part A will also be randomized 1 :1 to a KPL-404 treatment arm in Part B (without unblinding to prior treatment assignment). Both KPL-404 dosing groups include an 800 mg loading dose on Day 1 . SC = subcutaneous; q2wk = every other week; q4wk = every four weeks; R = Randomization; ESSDAI = EULAR Sjogren’s Syndrome Disease Activity Index; LD = loading dose.

[0041] FIGS. 2A-2C are graphs showing simulated PK Profiles for KPL-404 via SC Administration with 800 mg Loading Dose and 400 mg dosing at Intervals qwk, q2wk, and q4wk. FIG. 2A shows simulation for median weight of 70.5 kg and a SD of 13.5 kg (truncated between 50 kg and 100 kg). FIG. 2B shows a simulation for a weight of 40 kg. FIG. 2C shows a simulation for a weight of 150 kg. Lines: median simulated PK profiles; black dashed line = TDAR suppression of 2 pg / mL.

[0042] FIGS. 3A and 3B are graphs showing median PK profiles with 90% prediction intervals for 400 mg q4wk without a loading dose (FIG. 3A) and with a loading dose of 800 mg (FIG. 3B).

[0043] FIGS. 4A and 4B are graphs showing median PK profiles with 90% prediction intervals for 500 mg q4wk without a loading dose (FIG. 4A) and with a loading dose of 1000 mg (FIG. 4B).

[0044] FIGS. 5A and 5B are graphs showing median PK profiles with 90% prediction intervals for 600 mg q4wk without a loading dose (FIG. 5A) and with a loading dose of 1000 mg (FIG. 5B).

[0045] Detailed Description

[0046] The disclosure features methods of treating, reducing, or inhibiting Sjogren’s disease in a subject in need thereof by administering a pharmaceutical composition containing an anti-CD40 antibody or antigen binding fragment thereof. The subject may be treated by administration of an anti-CD40 antibody or antigen binding fragment thereof at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce one or more symptoms of Sjogren’s disease, as described herein. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 50 mg to about 1000 mg. For example, the antibody or antigen binding fragment thereof may be administered at a dosage of about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 100 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 200 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 300 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 400 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 500 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 600 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 700 mg. The antibody or antigen-binding fragment thereof may be administered at a dosage of about 800 mg. The antibody or antigen-binding fragment thereof may be administered about once per week, once every two weeks, once every three weeks, or once every four weeks. The subject may be treated by administration (e.g., subcutaneously) of 400 mg about once per week (e.g., once every 7 days), once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 400 mg once per week. In some embodiments, the method includes administration (e.g., subcutaneously) of 400 mg once every two weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 400 mg once every four weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 500 mg once per week. In some embodiments, the method includes administration (e.g., subcutaneously) of 500 mg once every two weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 500 mg once every four weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 600 mg once per week. In some embodiments, the method includes administration (e.g., subcutaneously) of 600 mg once every two weeks. In some embodiments, the method includes administration (e.g., subcutaneously) of 600 mg once every four weeks. In some embodiments, the antibody or antigen-binding fragment thereof is administered (e.g., subcutaneously, intravenously, or intrathecally) at a dosage of about 1 mg / kg to about 20 mg / kg (e.g., about 5 mg / kg to about 20 mg / kg, e.g., about 5 mg / kg to about 10 mg / kg, e.g., about 5.5 mg / kg to about 8.5 mg / kg, e.g., about 6 mg / kg to about 8 mg / kg, e.g., about 6.5 mg / kg to about 7.5 mg / kg, e.g., about 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, 16.5 mg / kg, 17 mg / kg, 17.5 mg / kg, 18 mg / kg, 18.5 mg / kg, 19 mg / kg, 19.5 mg / kg, or 20 mg / kg).

[0047] The methods described herein may include administering (e.g., subcutaneously, intravenously, or intrathecally) a loading dose (e.g., a first dose) that includes about 50 mg to about 1000 mg (e.g., about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg, e.g., 200 mg, 400 mg, 600 mg, or 800 mg) of the antibody or antigen-binding fragment thereof. In some embodiments, the loading dose of the antibody or antigen-binding fragment thereof is administered (e.g., subcutaneously, intravenously, or intrathecally) at a dosage of about 1 mg / kg to about 20 mg / kg (e.g., about 5 mg / kg to about 20 mg / kg, e.g., about 5 mg / kg to about 10 mg / kg, e.g., about 11 .5 to about 14.5 mg / kg, e.g., about 1 mg / kg, 1 .5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5. mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg,

[0048] 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, 16.5 mg / kg, 17 mg / kg,

[0049] 17.5 mg / kg, 18 mg / kg, 18.5 mg / kg, 19 mg / kg, 19.5 mg / kg, or 20 mg / kg). In some embodiments, a loading dose is not administered. The loading dose may be higher than the maintenance dose. The loading dose may be lower than the maintenance dose. The method may include administering (e.g., subcutaneously, intravenously, or intrathecally) one or more maintenance doses that include about 100 mg to about 1 ,000 mg of the antibody, e.g., about 100 mg, 200 mg, or 400 mg of the antibody or antigen-binding fragment thereof. For example, the method may include administering (e.g., subcutaneously) a loading dose of about 800 mg and one or more maintenance doses of about 400 mg once per week. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 800 mg and one or more maintenance doses of about 400 mg once every two weeks. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 800 mg and one or more maintenance doses of about 400 mg once every four weeks. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 1000 mg and one or more maintenance doses of about 400 mg once per week. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 1000 mg and one or more maintenance doses of about 400 mg once every two weeks. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 1000 mg and one or more maintenance doses of about 400 mg once every four weeks. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 1000 mg and one or more maintenance doses of about 500 mg once per week. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 1000 mg and one or more maintenance doses of about 500 mg once every two weeks. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 1000 mg and one or more maintenance doses of about 500 mg once every four weeks. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 1000 mg and one or more maintenance doses of about 600 mg once per week. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 1000 mg and one or more maintenance doses of about 600 mg once every two weeks. As another example, the method may include administering (e.g., subcutaneously) a loading dose of about 1000 mg and one or more maintenance doses of about 600 mg once every four weeks. As another example, the method may include administering (e.g., subcutaneously) about 400 mg once per week without a loading dose. As another example, the method may include administering (e.g., subcutaneously) about 400 mg once every two weeks without a loading dose. As another example, the method may include administering (e.g., subcutaneously) about 400 mg once every four weeks without a loading dose. As another example, the method may include administering (e.g., subcutaneously) about 500 mg once per week without a loading dose. As another example, the method may include administering (e.g., subcutaneously) about 500 mg once every two weeks without a loading dose. As another example, the method may include administering (e.g., subcutaneously) about 500 mg once every four weeks without a loading dose. As another example, the method may include administering (e.g., subcutaneously) about 600 mg once per week without a loading dose. As another example, the method may include administering (e.g., subcutaneously) about 600 mg once every two weeks without a loading dose. As another example, the method may include administering (e.g., subcutaneously) about 600 mg once every four weeks without a loading dose. The maintenance dose may be, for example, about 100 mg to about 1 ,000 mg (e.g., about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg, e.g., 200 mg, 400 mg, 600 mg, or 800 mg). The maintenance dose may be administered at a dosage of about 1 mg / kg to about 20 mg / kg (e.g., about 5 mg / kg to about 20 mg / kg, e.g., about 5 mg / kg to about 10 mg / kg, e.g., about 5.5 mg / kg to about 8.5 mg / kg, e.g., about 6 mg / kg to about 8 mg / kg, e.g., about 6.5 mg / kg to about 7.5 mg / kg, e.g., about 1 mg / kg, 1 .5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, 16.5 mg / kg, 17 mg / kg, 17.5 mg / kg, 18 mg / kg, 18.5 mg / kg, 19 mg / kg, 19.5 mg / kg, or 20 mg / kg). The pharmaceutical composition contains an anti-CD40 antibody or an antigen-binding fragment thereof that can block the ability of CD40 to bind CD154 and do so without activating the cell expressing CD40 (e.g., a B cell). Anti-CD40 treatment can also attenuate T-cell function, such as T-cell cytotoxicity (e.g., via CD40 blockade on antigen presenting cells), which can be therapeutic against Sjogren’s disease.

[0050] In general, the antibody or antigen-binding fragment thereof is derived from the murine 2C10 antibody and includes humanized variants thereof, e.g., as described in PCT Pub. Nos. WO 2012 / 125569 and WO 2017 / 040932, which are herein incorporated by reference in their entirety. The methods and the pharmaceutical compositions used therein are described in more detail below.

[0051] Antibodies and Antigen-Binding Fragments Thereof

[0052] The methods described herein include administration of an antibody or antigen-binding fragment thereof, e.g., derived from the murine 2C10 antibody. The heavy chain variable regions, light chain variable regions, and CDRs of certain anti-CD40 antibodies described herein are shown in Table 1. Table 1: 2C10 and KPL-404 antibody sequences

[0053]

[0054] In certain embodiments, the antibody or antigen-binding fragment thereof includes a heavy chain variable region including an amino acid sequence 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 99%, about 70%, about 75%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identity to the heavy chain variable region amino acid sequence as set forth in SEQ ID NO: 9.

[0055] In certain embodiments, the antibody or antigen-binding fragment thereof includes a light chain variable region including an amino acid sequence 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 99%, about 70%, about 75%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identity to a light chain variable region amino acid sequence as set forth in SEQ ID NO: 10.

[0056] In certain embodiments, the antibody or antigen-binding fragment thereof includes both a heavy chain variable region including an amino acid sequence 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 99%, about 70%, about 75%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identity to a heavy chain variable region amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region including an amino acid sequence 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 99%, about 70%, about 75%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identity to a variable light chain amino acid sequence as set forth in SEQ ID NO: 10.

[0057] In certain embodiments, the antibody or antigen-binding fragment thereof includes a heavy chain region including an amino acid sequence 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 99%, about 70%, about 75%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identity to a heavy chain with the amino acid sequence as set forth in SEQ ID NO: 1 1 , and a light chain region including an amino acid sequence 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 99%, about 70%, about 75%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identity to the light chain amino acid sequence as set forth in SEQ ID NO: 12.

[0058] In certain embodiments, the antibody or antigen-binding fragment thereof includes a heavy chain variable region including an amino acid sequence 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 99%, about 70%, about 75%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% sequence identity to a heavy chain variable region amino acid sequence as set forth in any one of SEQ ID NOs: 13, 14, 16, 17, or 18, and a light chain variable region including an amino acid sequence 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 99%, about 70%, about 75%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% sequence identity to a variable light chain amino acid sequence as set forth in any one of SEQ ID NOs: 15, 19, 20, or 21 .

[0059] In certain embodiments, a heavy chain variable region of the antibody or antigen-binding fragment thereof includes complementarity determining regions (CDRs) that are 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 99%, about 70%, about 75%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to the CDRs of a heavy chain variable region of the KPL-404 antibody (CDR1 , CDR2 and CDR3 as set forth in SEQ ID NOs: 3, 4, 5, respectively).

[0060] In certain embodiments, the light chain variable region of the antibody or antigen-binding fragment thereof includes CDRs that are 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 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to the CDRs of a light chain variable region of the KPL-404 antibody (CDR1 , CDR2 and CDR3 as set forth in SEQ ID NOs: 6, 7, 8, respectively).

[0061] In certain embodiments, the heavy chain variable region includes the CDRs as set forth in SEQ ID Nos: 3-5, respectively, and the light chain variable region includes the CDRs as set forth in SEQ ID Nos: 6-8, respectively.

[0062] In certain embodiments, the heavy chain variable region has at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or at least 100%) sequence identity to SEQ ID NO: 9 and the CDRs set forth in SEQ ID NOs: 3-5, respectively, and the light chain variable region has at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or at least 100%) sequence identity to SEQ ID NO: 10 and the CDRs set forth in SEQ ID NOs: 6-8, respectively.

[0063] Also within the scope of the disclosure are antibodies or antigen-binding fragments thereof in which specific amino acids have been substituted, deleted, or added. These alterations do not have a substantial effect on the peptide’s biological properties such as binding activity. For example, antibodies may have amino acid substitutions in the framework region, such as to improve binding to the antigen. In another example, a selected, small number of acceptor framework residues can be replaced by the corresponding donor amino acids. The donor framework can be a mature or germline human antibody framework sequence or a consensus sequence. Guidance concerning how to make phenotypically silent amino acid substitutions is provided in, e.g., Bowie et al. (Science, 247: 1306- 1310, 1990), Cunningham et al. (Science, 244: 1081-1085, 1989), Ausubel (ed.) (Current Protocols in Molecular Biology, John Wiley and Sons, Inc., 1994), T. Maniatis, E. F. Fritsch and J. Sambrook (Molecular Cloning: A Laboratory Manual, Cold Spring Harbor laboratory, Cold Spring Harbor, N.Y., 1989), Pearson (Methods Mol. Biol. 243:307-31 , 1994), and Gonnet et al. (Science 256:1443-45, 1992); each of which is incorporated herein by reference.

[0064] The polypeptides described herein may be a functionally active variant of the antibodies or antigen-binding fragments thereof disclosed herein, e.g., with less than about 30%, about 25%, about 20%, about 15%, about 10%, about 5% or about 1 % amino acid residues substituted or deleted but that retain essentially the same immunological properties including, but not limited to, binding to CD40.

[0065] In some embodiments, the dissociation constant (KD) of the antibody or antigen-binding fragment thereof is less than about 1 x 108, e.g., less than about 1 x 109.

[0066] The antibodies or antigen-binding fragments thereof may also include one or more analogs of an amino acid (including, for example, non-naturally occurring amino acids, amino acids which only occur naturally in an unrelated biological system, modified amino acids from mammalian systems etc.), polypeptides with substituted linkages, as well as other modifications known in the art. Indications

[0067] The methods described herein include administration of a pharmaceutical composition containing an antibody or antigen-binding fragment as described herein to a subject with Sjogren’s disease in an in vivo protocol (e.g., therapeutic or prophylactic) for the treatment of, or to reduce, inhibit, or mitigate one or more symptoms of, Sjogren’s disease. The anti-CD40 antibodies or antigen-binding fragments thereof can be administered to treat Sjogren’s disease or to treat or reduce the likelihood of developing one or more symptoms of Sjogren’s disease.

[0068] Sjogren’s disease is an autoimmune disease that affects the body’s moisture producing glands, including the lacrimal (tear) and salivary glands. A subject with Sjogren’s disease may present one or more symptoms or sequelae associated with the disease, such as fatigue, dry eyes, dry mouth, joint pain, trouble sleeping, eye discomfort, muscle pain, dry skin, vaginal dryness, chronic cough, numbness (e.g., in the arms and legs), and dry nose.

[0069] The methods described herein may be used to treat Sjogren’s disease, e.g., by reducing the occurrence or severity of one or more symptoms or associated sequelae of Sjogren’s disease, as described herein.

[0070] The methods described herein may inhibit or reduce (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) one or more sequelae associated with Sjogren’s disease. The method may reduce the severity or intensity of one or more symptoms of Sjogren’s disease. In some embodiments, the inhibition or reduction of symptoms or sequelae is measured with respect to a control. In some embodiments, the inhibition or reduction of symptoms or sequelae of Sjogren’s disease is measured with respect to a control (e.g., relative to the subject prior to treatment). In some embodiments, a control is indicative of the one or more symptoms of Sjogren’s disease in the subject before the treatment (also referred to as a baseline). In some embodiments, the control is indicative of the one or more symptoms of Sjogren’s disease as determined by evaluating health information from Sjogren’s disease patients overtime, demonstrating the natural progress of the condition, which can be obtained, for example, from a natural history study of Sjogren’s disease. In some embodiments, a control is indicative of the one or more symptoms of Sjogren’s disease in a control subject with the same disease status without treatment. In some embodiments, a control is indicative of the one or more symptoms of Sjogren’s disease in a subject with the same disease status, who is treated with a placebo. In some embodiments, a control is indicative of a disease state in a subject having the disease, who receives a standard of care therapy in absence of administration of a humanized anti-CD40 antibody or antigen-binding fragment thereof. The reduction may include a reduction in frequency and / or intensity of symptoms.

[0071] The methods described herein may be used in combination with immunosuppression (e.g., by co-ad ministration with an immunosuppressive agent).

[0072] Pharmaceutical compositions

[0073] Featured are methods of treating, reducing, or inhibiting Sjogren’s disease in a subject in need thereof, as described herein, by administration of a pharmaceutical composition containing an antibody or antigen-binding fragment thereof as described herein (e.g., an antibody or antigen-binding fragment thereof containing a heavy chain variable region having at least 80%, 85%, 90%, 95%, 97%, 99%, or 100% sequence identity to SEQ ID NO: 9 and a light chain variable region having at least 80%, 85%, 90%, 95%, 97%, 99%, or 100% sequence identity to SEQ ID NO: 10) formulated together with a pharmaceutically acceptable carrier. The antibody or antigen-binding fragment thereof can be formulated in a pharmaceutical composition in a concentration of about 50 to about 300 mg / mL, and optionally, in a volume of about 0.5 mL to about 2.0 mL (e.g., about 1 .0 mL). The composition can be administered to the subject prior to the development of symptoms of Sjogren’s disease prior to the diagnosis of Sjogren’s disease (e.g., in a subject predisposed to develop Sjogren’s disease), or after the development of one or more symptoms of Sjogren’s disease or a diagnosis of Sjogren’s disease.

[0074] The antibody or antigen-binding fragment thereof (e.g., KPL-404) may be incorporated into a pharmaceutical composition (e.g., in a concentration of about 50 mg / mL to about 300 mg / mL, such as about 100 mg / mL or about 200 mg / mL) including polysorbate 20, acetate, and one or more polar excipients. The polar excipient may be or may include, for example, a sugar, a polyol, or an amino acid. In some embodiments, the sugar is, for example, sucrose, trehalose, fructose, lactose, dextrose, or mannitol. In some embodiments, the polyol is, for example, polyethylene glycol or sorbitol. In some embodiments, the amino acid is one or more of alanine, arginine, aspartic acid, asparagine, carnitine, citrulline, ornithine, glycine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine. The acetate may include, for example, sodium acetate (e.g., in salt form) or acetate in its ionic form. In some embodiments, the polar excipient is, for example sucrose, arginine, glutamate, sorbitol, or a combination thereof. In some embodiments, the polar excipient is sucrose. In some embodiments the polar excipient is arginine. In some embodiments the polar excipient is glutamate. In some embodiments, the polar excipient is a mixture of arginine and glutamate. In some embodiments, the polar excipient is sorbitol.

[0075] The pharmaceutical composition can include from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM acetate, from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM), or from about 1% (w / v) to about 10% (w / v) (e.g., about 2% (w / v) to about 8% (w / v), e.g., about 1 % (w / v), 1 .5 % (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v), 5% (w / v), 5.5% (w / v), 6% (w / v), 6.5% (w / v), 7% (w / v), 7.5% (w / v), 8% (w / v), 8.5% (w / v), 9% (w / v), 9.5% (w / v), 10% (w / v), e.g., about 2.5% (w / v) or about 7% (w / v)) of the polar excipient, and from about 0.001% (w / v) to about 0.1% (w / v) (e.g., about 0.001% (w / v), 0.002% (w / v), 0.003% (w / v), 0.004% (w / v), 0.005% (w / v), 0.006% (w / v), 0.007% (w / v), 0.008% (w / v), 0.009% (w / v), 0.01% (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v), or 0.1% (w / v) polysorbate 20. The pharmaceutical composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., about 5.4 to about 5.6; e.g., about 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0. For example, the pH may be about 5.4.

[0076] For example, the pharmaceutical composition can include from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) sodium acetate, from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM) arginine, from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM) glutamate, and from about 0.001 % (w / v) to about 0.1 % (w / v) (e.g., about 0.002% (w / v), 0.003% (w / v), 0.004% (w / v), 0.005% (w / v), 0.006% (w / v), 0.007% (w / v), 0.008% (w / v), 0.009% (w / v), 0.01 % (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v), or 0.1 % (w / v) polysorbate 20. The pharmaceutical composition may have a pH of from about 5.0 to about 6.0. For example, the pH may be about 5.4.

[0077] The pharmaceutical composition can include an amount of an anti-CD40 antibody or antigenbinding fragment thereof described herein (e.g., KPL-404), such as about 50 mg / mL to about 300 mg / mL.

[0078] The antibody or antigen-binding fragment thereof (e.g., KPL-404) may also be incorporated into a pharmaceutical composition (e.g., in a concentration of about 100 mg / mL to about 300 mg / mL, such as 200 mg / mL).

[0079] The antibody or antigen-binding fragment thereof may be provided in a container including a pharmaceutical composition as described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container holds a pharmaceutical composition as described herein, e.g., that is effective for treating the condition, and may have a sterile access port. For example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle. The label on or associated with the container indicates that the composition is used for treating the condition of choice. The kit may further include a second container with a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. The antibody or antigen-binding fragment thereof may be present in the container at a concentration of from about 50 mg / mL to about 300 mg / mL (e.g., about 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, or 300 mg / mL), such as at a concentration of about 100 mg / mL or about 200 mg / mL.

[0080] The composition may be formulated in a single use vial with about 1 .0 mL or 2.0 mL extractable volume. The composition can be formulated in a volume of about 0.1 mL to about 2.0 mL (e.g., about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1 .0 mL, 1.1 mL, 1 .2 mL, 1 .3 mL, 1 .4 mL, 1 .5 mL, 1 .6 mL, 1 .7 mL, 1 .8 mL, 1 .9 mL, or 2.0 mL), such as a volume of about 1 .0 mL.

[0081] Routes of Administration and Methods of Treatment

[0082] A composition as described herein can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending upon the desired results. Administration may be parenteral, intravenous, intrathecal, subcutaneous, oral, topical, local, intramuscular, intradermal, transdermal, subdermal, rectal, spinal, or epidermal. Intravenous delivery by continuous infusion is one exemplary method for administering the present antibodies or antigen-binding fragments thereof. Another exemplary method is by subcutaneous administration.

[0083] The composition described herein may include a pharmaceutically acceptable diluent. Pharmaceutically acceptable diluents include, for example, saline and aqueous buffer solutions.

[0084] Parenteral administration can include modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.

[0085] The methods described herein may include administration of the pharmaceutical composition by infusion or by intravenous or subcutaneous administration.

[0086] The disclosure features methods of treating, reducing, or inhibiting Sjogren's disease in a subject in need thereof by administering a pharmaceutical composition containing an anti-CD40 antibody or antigen binding fragment thereof at a dosage of about 100 mg to about 1000 mg (e.g., 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg). The method may include administering (e.g., subcutaneously) a loading dose (e.g., a first dose) that includes about 100 mg to about 1000 mg (e.g., about 400 mg, 600 mg or 800 mg, e.g., as two doses of 200 mg each, 150 mg each or 400 mg each, respectively) of the antibody or antigen-binding fragment thereof. The method may include administering (e.g., subcutaneously) one or more doses (e.g., as maintenance doses) that include about 100 mg to about 800 mg (e.g., 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg) of the antibody or antigen-binding fragment thereof, with or without a loading dose. The method may include administering (e.g., subcutaneously) a loading dose (e.g., an initial dose at the onset of treatment) of about 100 mg to about 1000 mg (e.g., about 200 mg to about 800 mg, e.g., 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg). In some embodiments, the method includes administering (e.g., subcutaneously) one or more maintenance doses of about 100 mg to about 800 mg (e.g., about 200 mg to about 400 mg, e.g., 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg), e.g., once per day, once per week, once every two weeks, once every three weeks, or once every four weeks, with or without a loading dose.

[0087] In some embodiments, the maintenance dose is provided to maintain a desired minimum blood, plasma, or serum concentration of the antibody or antigen-binding fragment thereof. For example, in some embodiments, it is desirable to maintain a minimum concentration (e.g., a trough concentration) of at least about 2 pg / mL, 5 pg / mL, 10 pg / mL, 20 pg / mL, 25 pg / mL (e.g., at least 30 pg / mL, 40 pg / mL, 50 pg / mL, 60 pg / mL, 70 pg / mL, 80 pg / mL, 90 pg / mL, 100 pg / mL, 110 pg / mL, 120 pg / mL, 130 pg / mL, 140 pg / mL, 150 pg / mL, 160 pg / mL, 170 pg / mL, 180 pg / mL, 190 pg / mL, 200 pg / mL, 210 pg / mL, 220 pg / mL, 230 pg / mL, 240 pg / mL, or 250 pg / mL, 260 pg / mL, 270 pg / mL, 280 pg / mL, 290 pg / mL, or 300 pg / mL (e.g., a range from about 2 pg / mL to about 5 pg / mL; from about 2 pg / mL to about 10 pg / mL; from about 2 pg / mL to about 20 pg / mL; from about 5 pg / mL to about 20 pg / mL; from about 10 pg / mL to about 20 pg / mL; or from about 10 pg / mL to about 50 pg / mL) of the antibody or antigen-binding fragment thereof in the blood, plasma, or serum of the subject. The method may include administering a maintenance dose (e.g., at a dosage of about 200 mg or 400 mg) of the antibody or antigen-binding fragment thereof. These maintenance doses can be repeatedly administered, e.g., once every week, once every two weeks, once every three weeks, or once every four weeks, or as needed. The maintenance dose can be administered to the subject for a treatment period of at least one month (e.g., for a treatment period of at least two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, or for the life of the subject). The timing of administration of the maintenance dose and / or the timing between maintenance doses may be selected based on the PK profile of the antibody or antigen-binding fragment thereof in, e.g., the blood, plasma, or serum of the subject.

[0088] In some embodiments, the method includes administering about 100 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 100 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 100 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 100 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0089] In some embodiments, the method includes administering about 200 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 200 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 200 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 200 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0090] In some embodiments, the method includes administering about 300 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 300 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 300 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 300 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0091] In some embodiments, the method includes administering about 400 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 400 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 400 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 400 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0092] In some embodiments, the method includes administering about 500 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 500 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 500 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 500 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0093] In some embodiments, the method includes administering about 600 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 600 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 600 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 600 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0094] In some embodiments, the method includes administering about 700 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 700 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 700 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 700 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0095] In some embodiments, the method includes administering about 800 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 800 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 800 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 800 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0096] In some embodiments, the method includes administering about 900 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 900 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 900 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 900 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0097] In some embodiments, the method includes administering about 1000 mg of the antibody or antigen-binding fragment thereof at frequency of about once every week. In some embodiments, the method includes administering about 1000 mg of the antibody or antigen-binding fragment thereof at frequency of about once every two weeks. In some embodiments, the method includes administering about 1000 mg of the antibody or antigen-binding fragment thereof at frequency of about once every three weeks. In some embodiments, the method includes administering about 1000 mg of the antibody or antigen-binding fragment thereof at frequency of about once every four weeks.

[0098] In one example, the antibody or antigen-binding fragment thereof may be administered (e.g., intravenously or intrathecally) at a dosage of about 1 mg / kg, 1 .5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg,

[0099] 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg,

[0100] 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, 16.5 mg / kg, 17 mg / kg,

[0101] 17.5 mg / kg, 18 mg / kg, 18.5 mg / kg 19 mg / kg, 19.5 mg / kg, or 20 mg / kg.

[0102] In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 5 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 5 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 5 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 5 mg / kg at a frequency of about once every four weeks.

[0103] In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 5.5 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 5.5 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 5.5 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 5.5 mg / kg at a frequency of about once every four weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 6 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 6 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about

[0104] 6 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 6 mg / kg at a frequency of about once every four weeks.

[0105] In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 6.5 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 6.5 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 6.5 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 6.5 mg / kg at a frequency of about once every four weeks.

[0106] In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 7 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 7 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about

[0107] 7 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 7 mg / kg at a frequency of about once every four weeks.

[0108] In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 7.5 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 7.5 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 7.5 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 7.5 mg / kg at a frequency of about once every four weeks.

[0109] In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 8 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 8 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about

[0110] 8 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 8 mg / kg at a frequency of about once every four weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 8.5 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 8.5 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 8.5 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 8.5 mg / kg at a frequency of about once every four weeks.

[0111] In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 9 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 9 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 9 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 9 mg / kg at a frequency of about once every four weeks.

[0112] In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 10 mg / kg at a frequency of about once every week. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 10 mg / kg at a frequency of about once every two weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 10 mg / kg at a frequency of about once every three weeks. In some embodiments, the method includes administering the antibody or antigen-binding fragment thereof at a dosage of about 10 mg / kg at a frequency of about once every four weeks.

[0113] The composition may be administered, e.g., once per day, once per week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the composition is administered during a treatment regimen of at least one day, one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, one year, or longer, for example, for the life of the subject. In one embodiment, the composition is administered to the subject until clinical remission is achieved or a minimum low disease activity is achieved.

[0114] In one example, the antibody or antigen-binding fragment thereof is administered subcutaneously at a concentration of about 2 mg / kg, about 5 mg / kg, or about 10 mg / kg, e.g., once every week.

[0115] In some embodiments, the composition may be administered during a treatment regimen of about 12 weeks, 26 weeks, 1 year, 2 years, 3 years, 4 years, 5 years, or longer, for example, for the life of the subject.

[0116] In some embodiments, the method includes using an efficacy metric to determine the efficacy of treatment. In one embodiment, the composition is administered to the subject until clinical remission or a reduction (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) in symptoms, such as dry mouth or dry eyes, is achieved or a minimum low disease activity is achieved. Clinical remission or reduction in symptoms may be assessed with one or more efficacy metrics.

[0117] The efficacy metric may include a EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score, e.g., as described in Seror et al. Ann Rheum Dis. 81 (7):979-989, 2022. The efficacy metric may include an ESSDAI score that decreases, e.g., by at least 3 following administration of the composition. The efficacy metric may include an ESSDAI score less than 5 following administration of the composition. The efficacy metric may include an improvement in ESSDAI score following administration of the composition. The efficacy metric may include a Sjogren's Tool for Assessing Response (STAR) score > 5 following administration of the composition. The efficacy metric may include improvement, following administration of the composition, in one of more of the individual STAR domains selected from the group consisting of systemic activity assessed by ESSDAI score, patient-reported outcome assessed by ESSPRI score, lacrimal gland function assessed by Schirmer’s test score, salivary gland function, and biological function assessed by IgG decrease of at least 10% or rheumatoid factor (RF) level decrease of at least 25%. For example, the efficacy metric may include IgG decrease of at least 10% or rheumatoid factor (RF) level decrease of at least 25% following administration of the composition. The efficacy metric may include an unstimulated salivary flow test. In an unstimulated salivary flow test, an increase of at least 25% following administration of the composition may be indicative of efficacy. Alternatively, an increase in unstimulated salivary flow following administration of the composition may be indicative of efficacy if no saliva was produced prior to administration of the composition. The efficacy metric may include an improvement in stimulated salivary flow following administration of the composition. The efficacy metric may include a Schirmer’s test, which is used to determine whether the eye produces enough tears to keep it moist (see, e.g., Schirmer, Otto. "Studies on the physiology and pathology of the secretion and drainage of tears." Albrecht von Graefes Arch Klin Ophthalmol 56: 197-291 , 1903). The subject may have a Schirmer’s test score of 10 mm or higher following administration of the composition. The efficacy metric may include an increase of 5 mm or more in Schrimer’s test score following administration of the composition if Schrimer’s test score was below 5 mm prior to administration of the composition or, alternatively, Schirmer’s test score > 5 mm following administration of the composition if Schrimer’s test score is 10 mm or higher prior to administration of the composition. The efficacy metric may include a EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) test, e.g., as described in Seroret al. Annals of the Rheumatic Diseases 70.6: 968-972, 2011 . The efficacy metric may include a decrease in the score of the ESSPRI test of at least 1 or at least 15% following administration of the composition. The efficacy metric may include a EuroQol 5 Dimension 5 Level (EQ-5D-5L) assessment. The EQ-5D-5L score may improve following administration of the composition. The efficacy metric may include a Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) score following administration of the composition. An increase in the FACIT-Fatique score may be observed following administration of the composition. The efficacy metric may include an Evaluator Global Assessment (EGA) test. The EGA score may improve following administration of the composition. The EGA test may include a score of 3 or less following administration of the composition. The EGA test may include a score or 2 or less following administration of the composition. The EGA test may include an EGA score of 1 following administration of the composition. The efficacy metric may include an Evaluator Global Assessment of Change (EGAC) score. The EGAC score may be from 0 to 2 following administration of the composition. The EGAC score may be from 0 to 1 following administration of the composition. The EGAC score may be 0 following administration of the composition. The efficacy metric may include a Patient Global Impression of Severity (PGIS) test. The PGIS score may be 3 or less following administration of the composition. The PGIS score may be 2 or less following administration of the composition. The PGIS score may be 1 following administration of the composition. The efficacy metric may include a Patient Global Impression of Change (PGIC) test. The PGIC score may be from 0 to 2 following administration of the composition. The PGIC score may be from 0 to 1 following administration of the composition. The PGIC score may be 0 following administration of the composition.

[0118] Combination Therapy

[0119] The pharmaceutical compositions administered in a method as described herein can be administered alone or in combination with one or more other therapeutic agents (e.g., a second therapeutic agent). In some embodiments, the pharmaceutical composition including the anti-CD40 antibody or antigen-binding fragment thereof can further include a second therapeutic agent, e.g., either conjugated or unconjugated to the antibody or its fragment. In one embodiment, the second agent is another monoclonal or polyclonal antibody or antigen-binding fragment thereof. In another embodiment, the second agent is an immunosuppressant. In one embodiment, the second agent may target a receptor or receptor complex other than CD40 on the surface of activated lymphocytes, dendritic cells or CD40-expressing cancer cells.

[0120] Such combination therapy can have an additive or synergistic effect on condition parameters (e.g., severity of a symptom, the number of symptoms, or frequency of symptoms).

[0121] The pharmaceutical composition may be administered concurrently with the second therapeutic agent. In another specific embodiment, the second therapeutic agent is administered prior to or subsequent to administration of the pharmaceutical composition containing the anti-CD40 antibody or antigen-binding fragment thereof.

[0122] The method may further include administration of a second agent, e.g., within six months of the administration of the antibody or antigen-binding fragment thereof.

[0123] The second agent may be, for example, an immunosuppressant.

[0124] The pharmaceutical compositions containing the antibodies or antigen-binding fragments described herein can be formulated or administered in combination with (e.g., at the same time or at a different time) an immunosuppressant. Examples of immunosuppressants include, but are not limited to, calcineurin inhibitors (e.g., a cyclosporin, such as, e.g., cyclosporin A (SANDIMMUNE®) and cyclosporine G tacrolimus (PROGRAF®, PROTOPIC®)), an mTor inhibitor (e.g., sirolimus (RAPAMUNE®, NEORAL®), temsirolimus (TORISEL®), zotarolimus, and everolimus (CERTICAN®)), fingolimod (GILENYA™), myriocin, alemtuzumab (CAMPATH®, MABCAMPATH®, CAMPATH-1 H®), rituximab (RITUXAN®, MABTHERA®), an anti-CD4 monoclonal antibody (e.g., HuMax-CD4), an anti- LFA1 monoclonal antibody (e.g., CD11a), an anti-LFA3 monoclonal antibody, an anti-CD45 antibody (e.g., an anti-CD45RB antibody), an anti-CD19 antibody (see, e.g., U.S. Patent Publication 2006 / 0280738), monabatacept (ORENCIA®), belatacept, indolyl-ASC (32-indole ether derivatives of tacrolimus and ascomycin), azathioprine (AZASAN®, IMURAN®), lymphocyte immune globulin and anti-thymocyte globulin [equine] (ATGAM®), mycophenolate mofetil (CELLCEPT®), mycophenolate sodium (MYFORTIC®), daclizumab (ZENAPAX®), basiliximab (SIMULECT®), cyclophosphamide (ENDOXAN®, CYTOXAN®, NEOSAR™, PROCYTOX™, REVIMMUNE™), prednisone, prednisolone, leflunomide (ARAVA®), FK778, FK779, 15-deoxyspergualin (DSG), busulfan (MYLERAN®, BUSULFEX®), fludarabine (FLUDARA®), methotrexate (RHEUMATREX®, TREXALL®), etanercept (ENBREL®), adalimumab (HUMIRA®), 6-mercaptopurine (PURINETHOL®), 15-deoxyspergualin (Gusperimus), LF15-0195, bredinin, brequinar, and muromonab-CD3 (ORTHOCLONE®).

[0125] The antibody or antigen-binding fragment thereof and the second therapeutic agent (e.g., an immunosuppressant) may be administered within one month of each other or within one week of each other.

[0126] Examples

[0127] The following examples of specific aspects for carrying out the present disclosure are offered for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way.

[0128] Example 1. Treatment of Sjogren’s Disease

[0129] INTRODUCTION

[0130] Background

[0131] Sjogren’s Disease is a chronic autoimmune rheumatic disease characterized by lymphocytic infiltration of exocrine glands and other organs in association with the production of various autoantibodies in the blood. In most cases this disorder develops insidiously over a period of months to years. Characteristic symptoms include dry eyes, dry mouth, fatigue, musculoskeletal pain and swelling of the major salivary glands. In some cases, the gradual and progressive damage and dysfunction of exocrine glands will result in whole-body dryness. Internal organ involvement occurs in about 25% of patients and the development of non-Hodgkin’s B-cell lymphomas represents the major complication of the disease.

[0132] The estimated prevalence of Sjogren’s Disease in the United States ranges between 0.4 to 3.1 million individuals, and Sjogren’s Disease is ranked as the second most common autoimmune rheumatic disease after rheumatoid arthritis. Sjogren’s Disease occurs more frequently in women, with a female-to-male ratio of 9:1 . The peak incidence is in the 40 to 55 years of age group.

[0133] CD40 is a membrane protein from the TNF receptor superfamily and is expressed by both immune and nonimmune cells. Its ligand, CD154, is expressed in a transitory form, particularly on the membrane surface of activated CD4+ T cells. CD154 is crucial for modulating several autoimmune processes, in which T- and B-lymphocytes co-stimulate. KPL-404, having a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 10, is a human monoclonal antibody inhibitor of the CD40 / CD154 co-stimulatory interaction. It blocks the interaction between CD40 and CD154 by binding to CD40.

[0134] Current Therapeutic Management of Sjogren’s Disease

[0135] The treatment of Sjogren’s Disease currently has no cure; therapy is tailored for each patient to reduce symptoms, avoid complications, and improve quality of life. Respondents to a recent survey conducted by the Sjogren's Disease Foundation reported using more than eight medications and treatments for their symptoms, which represents a heavy burden to the patients and society. Systemic and long-term use of steroids and immunosuppression medications bears unavoidable severe side effects. New safer and more efficacious therapeutics remain to be established in clinical studies.

[0136] KPL-404KPL-404 is a monoclonal antibody consisting of 2 heavy chains and 2 light chains covalently linked by disulfide bridges. It binds to CD40 with an affinity of 7.2 nM, and blocks CD40- mediated activation of B-cells.

[0137] Study Rationale

[0138] The current study will assess the efficacy and safety of KPL-404 versus placebo in participants with Sjogren’s Disease with moderate or high systemic disease activity. Kiniksa Pharmaceuticals, GmbH is developing KPL-404, a humanized immunoglobulin G4(lgG4) monoclonal antibody that binds CD40 and interferes with the CD40-CD154 costimulatory interaction, for the treatment of autoimmune diseases.

[0139] CD40 is a TNF-receptor superfamily member expressed on both immune and non-immune cells. It is primarily known as a costimulatory receptor that regulates the activity of dendritic cells, monocytes, platelets, macrophages, and B-cells, as well as nonhematopoietic cells such as myofibroblasts, fibroblasts, epithelial, and endothelial cells. A major role of CD40-CD154 interactions is to promote T-cell dependent B-cell differentiation and antibody production in response to antigens. Interactions between B-cell-expressed CD40 and CD154, predominantly expressed on activated CD4+ T-cells, promotes germinal center (GO) formation, immunoglobulin isotype switching, somatic hypermutation of the immunoglobulin to enhance affinity for antigen, and finally the formation of long- lived plasma cells and memory B cells.

[0140] In a variety of autoimmune diseases, dysregulated expression of components from the CD40 costimulatory system has been shown. For example, CD154 expression is elevated on various cell subsets (i.e., B-cells, T-cells, monocytes) from patients with systemic lupus erythematosus (SLE), and CD154 expression is elevated on circulating T-cells from patients with rheumatoid arthritis (RA) and psoriatic arthritis. CD154 overexpression on T-cells from RA patients correlates with poor clinical outcomes, including higher disease activity and fewer remissions. Additionally, soluble CD154 has also been found to be increased in several autoimmune conditions. Furthermore, a single nucleotide polymorphism in the sequence of CD40 leads to increased CD40 protein levels in the thyroid and is associated with disease in a subset of patients with Graves' disease. Finally, the presence of ectopic GCs in the target organs of autoimmune disease patients (e.g., salivary glands in Sjogren’s Disease, thyroid gland in Graves’ disease) has also been observed where GCs preferentially drive the affinity maturation and clonal selection of autoantibodies toward specific autoantigens and this process occurs downstream of the CD40-CD154 pathway.

[0141] Inhibition of CD40-CD154 costimulatory interaction in mouse models of autoimmune disease significantly suppressed disease frequency and / or pathology. Together, these results support a role for the CD40-CD154 costimulatory interaction in autoimmune disease and suggest that aberrant CD40 signaling could contribute to the initiation or maintenance of pathogenic autoimmune responses.

[0142] Given the broad spectrum of impact of CD40 signaling on the immune response and its potential role in a variety of autoimmune diseases, several molecules targeting the CD40-CD154 costimulatory interaction have been generated and evaluated in clinical settings. Trials with CD40- targeting therapeutics such as iscalimab (CFZ533; Novartis) have demonstrated efficacy in significantly improving disease activity scores in patients with Sjogren’s Disease and T3 / T4 levels in patients with Graves’ disease, providing external proof of concept and justification for targeting this pathway in autoimmune diseases. In a Phase 2, randomized, double-blind, placebo-controlled proof of concept study in patients with Sjogren’s Disease (St. Clair 2023), Dazodalibep, a CD40L antagonist, significantly decreased disease activity, achieving lower disease activity with 3- or 4-point improvements from baseline in EULAR Sjogren’s disease activity index (ESSDAI). The clinical trials to date show early signals of efficacy and early external proof of concept, raising the possibility that targeting CD40 could be a new way to address the unmet need in autoimmune disease, generally, and in Sjogren’s Disease, specifically.

[0143] There is an ongoing Phase 2 randomized, placebo-controlled trial of KPL-404 in rheumatoid arthritis (KPL-404-C211), in which participants received study drug or placebo for 12 weeks in 4 different cohorts.

[0144] • Cohort 1 : KPL-404, 2 mg / kg (or matching placebo) subcutaneous (SC) injection every two weeks (q2wk) (n=8: 3:1 active: place bo)

[0145] • Cohort 2: KPL-404, 5 mg / kg (or matching placebo) SC injection q2wk (n=8: 3:1 active:placebo)

[0146] • Cohort 3: (n=78 participants; 1 :1 :1) o 5 mg / kg SC once each week (qwk) o 5 mg / kg SC q2wk (weekly dosing with alternating administration of KPL-404 q2wk and placebo q2wk) o Placebo SC qwk

[0147] • Cohort 4: (n=51 participants; 3:2 active:placebo) o KPL-404 SC once every four weeks (q4wk; 600 mg loading dose at baseline followed by maintenance dosing 400 mg q4wk at Weeks 4 and 8) o Placebo SC q4wk

[0148] The trial is fully enrolled and investigational treatment is complete. There have been no reported suspected unexpected serious adverse reactions (SUSARs), and no Grade 3 (severe) or higher adverse events (AEs) causally related to study drug in this ongoing blinded trial to date. One adverse event of special interest (dental abscess) was reported.

[0149] In clinical trial experience to date, KPL-404 has demonstrated a favorable safety profile, with no laboratory or clinical evidence of immunosuppression, serious infections, herpes zoster infections, or thromboembolic events. With ongoing surveillance, safety risks associated with investigational use of KPL-404, at the proposed doses in adult Sjogren’s Disease patients, are believed to be acceptable, and the risk benefit ratio supports the investigation of this agent for the treatment of Sjogren’s Disease in participants providing informed consent.

[0150] Dose Justification

[0151] Pharmacokinetics: To evaluate dosing for further Phase 2 clinical studies, a population PK model, developed using KPL-404 concentration-time data from healthy volunteers in Study KPL-404-C101 , was updated using anonymized PK data from the ongoing Phase 2 rheumatoid arthritis (RA) study (KPL-404-C211) Cohorts 1-4. The model simulated PK profiles for KPL-404 weight-based and fixed-mg dose regimens, via SC administration, with loading dose of 800 mg and subsequent dosing of 400 mg at intervals of qwk, q2wk, and q4wk, in patients with active RA.

[0152] Dose Selection: This study seeks to evaluate safety, effectiveness, and pharmacokinetics for KPL-404 at 2 dose levels.

[0153] Dose Level 1 (400 mg SC q2wk): This is the highest level to be used in this study. This dose regimen provides an opportunity to establish a clinical and biomarker response reasonably achievable with practical intermittent subcutaneous dosing of KPL-404 every 2 weeks, taking advantage of the high-concentration liquid formulation containing 200 mg / mL, which can deliver an KPL-404 dose of 400 mg SC in a single 2 mL injection. An 800 mg SC loading dose (2 ml x 2) will be used to rapidly achieve steady state earlier in the treatment period. PK modeling predicts that this regimen will achieve median Cmax serum concentrations of KPL-404 of 104.7 pg / mL (40.8 to 195.9 pg / mL at 95% confidence interval [Cl]) with a trough concentration (Ctrough) of 78.1 pg / mL (26.3 to 151 .5 pg / mL at 95% Cl). The median Ctrough is approximately 40-fold above what is needed to suppress TDAR (2 pg / mL). Should a participant at the lowest body weight of 40 kg enroll and receive the 400 mg SC q2wk dose level, the PK model predicted median Cmax and AUC values were 169.1 ug / mL (76 to 285.6 pg / mL at 95% Cl) and 2145.5 daypg / mL (983.5 to 3588.1 daypg / mL at 95% Cl), respectively. The upper bounds of the 95% Cis correspond to ~21% (by Cmax) and ~41% (by AUC) of the NOAEL limits from the non-clinical study.

[0154] Dose Level 2 (400 mg SC q4wk): This dose regimen is estimated to represent a monthly- administered “effective” dose level, providing trough plasma concentrations that are at least an order of magnitude higher than that required to maintain > 90% peripheral B-cell CD40 receptor occupancy and to sustain TDAR suppression in the target patient population with a convenient and practical dosing regimen. Specifically, simulated PK profiles predict that an KPL-404 SC loading dose of 800 mg followed by 400mg SC q4wk, will result in steady state median serum concentrations between approximately 50 pg / mL and 20 pg / mL, with trough concentrations above 3 pg / mL in 90% of participants.

[0155] Benefit-Risk Assessment Nonclinical studies have established a NOAEL at exposures approximately 4 to 8-fold greater

[0156] (by AUC and Cmax, respectively) than those predicted in a lowest eligible body weight participant receiving the highest dose regimen of KPL-404 in this study. A completed Phase 1 study and an ongoing Phase 2 rheumatoid arthritis study have provided safety information that demonstrate plasma concentrations and exposures, up to those associated with the 5 mg / kg SC weekly dose level, are well tolerated. These data, combined with an established biological basis for expected beneficial mechanism of action, support the belief that KPL-404 has the potential to improve outcomes in this study population with low risk of significant adverse events.

[0157] STUDY OBJECTIVES

[0158] Table 2: Efficacy objectives and endpoints

[0159] INVESTIGATIONAL PLAN

[0160] Overall Study Design

[0161] This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of KPL-404 in participants with Sjogren’s Disease with moderate or high systemic disease activity (ESSDAI >5 based only on the biological, hematological, articular, cutaneous, glandular, lymphadenopathy, and constitutional organ domains).

[0162] Screening Period

[0163] After signing the informed consent form (ICF), participants will enter the study screening period of up to 6 weeks (Day -42 up to Day -1). During the screening period, assessment of disease characteristics, baseline therapy, and the pretreatment workup will be completed. Screening assessments may be repeated at the discretion of the Investigator during the screening period.

[0164] As appropriate, participants who screen fail may be rescreened once for this study with medical monitor approval. Rescreened participants will be assigned a new participant number.

[0165] Part A - Randomized, Double-bind, Placebo-controlled Period

[0166] During the randomized, double-blind, placebo-controlled period (Part A), participants will be randomized 1 :1 :1 to receive subcutaneous (SC) administration of KPL-404 400 mg dose level (at q2wk or q4wk frequency) or matching placebo q2wk:

[0167] KPL-404400mg q2wk: A loading dose of 800 mg KPL-404 is administered at the Baseline Visit (Day 1) as 2 SC injections of 400 mg each, followed by single SC injections of KPL-404400 mg SC q2wk thereafter, up to and including Week 22. • KPL-404400mg q4wk: A loading dose of 800 mg KPL-404 is administered at the Baseline Visit (Day 1) as 2 SC injections of 400 mg each, followed by a single SC injection q2wk thereafter, up to and including Week 22. In this treatment group

[0168] SC injections every 2 weeks will alternately administer placebo or KPL-404 to provide active drug q4wk while maintaining treatment concealment.

[0169] • Placebo: A matched volume placebo loading dose is administered at the Baseline Visit (Day 1) as 2 SC injections, followed by single SC injections of placebo q2wk thereafter, up to and including Week 22.

[0170] At the Baseline Visit (Day 1), participants will receive a loading dose of 2 SC injections of KPL-404 (400 mg + 400 mg) or matching placebo, followed by the assigned study drug through Week 24. Placebo volume will be matched to KPL-404.

[0171] Part A KPL-404 doses or placebo at the Baseline Visit will be administered by SC injection at the study site. The first injection of KPL-404 loading dose at the Baseline Visit will be administered at the study site by study site staff. The second injection of KPL-404 loading dose at the Baseline Visit will be prepared and administered by the participant or the participant’s caregiver after adequate training and under the supervision of study site personnel.

[0172] Part A KPL-404 doses or placebo at the Baseline, and the Week 2, 4, 8, 12, 16 and 20 Visits will be administered by SC injection at the study site by study site personnel (except for the 2ndbaseline loading dose and Week 2 Visit injection administered by the participant or trained caregiver, under site staff supervision as part of SC injection training). Part A study drug doses at Weeks 6, 10, 14, 18 and 22 may be administered at home by either the participant or trained caregiver. As permitted by local regulations and site policy, study drug (KPL-404 or placebo) may, alternatively, be administered to the participant by a visiting health provider in the participant’s home.

[0173] Participants will be observed for 60 minutes after dosing in-clinic at Baseline Visit, and for 30 minutes after other dose administrations in Part A performed in clinic.

[0174] Throughout Part A, participants will be evaluated with efficacy and safety assessments, and samples for PK, PD (US clinical sites only) and biomarker analyses will be collected.

[0175] Participants who complete Part A on treatment with the Week 24 Visit will continue into an active treatment extension period (Part B), in which participants will remain blinded to treatment frequency only (q2wk or q4wk).

[0176] Part B - Active Treatment Extension Period

[0177] During the active treatment extension period, participants will receive an additional 24 weeks of KPL-404400 mg SC at q2wk or q4wk frequency, blinded to treatment frequency only (q2wk or q4wk):

[0178] • KPL-404400mg q2wk: Single SC injections of KPL-404 400 mg SC q2wk thereafter, up to and including Week 46.

[0179] • KPL-404400mg q4wk: Single SC injection q2wk thereafter, up to and including Week 46. In this treatment group SC injection every 2 weeks will alternately administer placebo or KPL-404 to provide active drug q4wk while maintaining treatment concealment. Participants who received KPL-404 in Part A will continue to receive the same KPL-404 dose level and frequency in Part B. Participants who were randomized to receive placebo in Part A will be randomized 1 :1 at Baseline to receive either KPL-404 400 mg SC q2wk or 400 mg SC q4wk in Part B, without unblinding to prior treatment assignment in Part A.

[0180] The treatment frequency assignment will remain concealed from the participant, Investigator / site-staff, the CRO, and Sponsor staff. To maintain the blind relative to frequency of dose administration of active agent, all participants will receive SC injections q2wk; those assigned to the KPL-404 q4wk dose level will receive alternating administration of KPL-404 or placebo.

[0181] Part B study drug (KPL-404 / placebo) doses at the Week 24, 26, 28, 32, 36, 40 and 44 Visits will be administered by SC injection at the study site by study site personnel. Part B study drug (KPL- 404 / placebo) doses at Weeks 30, 34, 38, 42 and 46 may be administered at home by either the participant or trained caregiver. As permitted by local regulations and site policy, study drug (KPL-404 or placebo) may, alternatively, be administered to the participant by a visiting health provider in the participant’s home.

[0182] Participants will be observed for 60 minutes after dosing in-clinic at Week 24 and for 30 minutes after other dose administrations performed in clinic.

[0183] Throughout Part B, participants will be evaluated with efficacy and safety assessments, and samples for PK, PD (US clinical sites only) and biomarker analyses will be collected.

[0184] Part C - Safety Follow-up Period

[0185] Participants who complete the active treatment extension period at the Week 48 Visit will enter Part C, an 8-week Safety Follow-up Period, in which no active or placebo study drug is administered to any participants.

[0186] Safety follow-up visits should occur for all participants.

[0187] If a participant prematurely discontinues study drug administration prior to completion of Part A (at any point before the Week 24 Visit), there will be several visits that follow, namely an EOT Visit- Part A visit as soon as possible (within 2 weeks of the last study drug administration) and the remaining scheduled clinic visits. All participants who prematurely discontinue study drug administration in Part A will be followed for the 8-week safety follow-up period.

[0188] Participants who prematurely discontinue study drug administration in Part B (at any point after the Week 24 Visit and prior to the Week 48 Visit) will have an EOT Visit-Part B within approximately 2 weeks from last dose of study drug, and then enter the Safety Follow-up Period for 8 additional weeks, with visits as specified in the SoA.

[0189] All participants who complete study drug administration in Part A (through Week 24) and do not continue to Part B will have an EOT Visit-Part A, then enter the Safety Follow-up Period for 8 additional weeks, with visits as specified in the SoA.

[0190] All participants who discontinue study drug early should be followed until resolution of all their AEs or until the End of Study (EOS) visit. Number of Participants

[0191] Approximately 200 participants will be enrolled into the randomized, double-blind, placebo- controlled period (Part A) with approximately 67 participants assigned to each of the 3 treatment arms. Discontinued participants will not be replaced.

[0192] SELECTION AND WITHDRAWAL OF PARTICIPANTS

[0193] Approximately 200 participants with Sjogren’s Disease with moderate or high systemic disease activity will be enrolled at approximately 75 sites globally. Participants will be assigned to study drug only if they meet all the inclusion criteria and none of the exclusion criteria.

[0194] Deviations from the inclusion and exclusion criteria are not allowed because such deviations can potentially jeopardize the scientific integrity of the study, regulatory acceptability, or participant safety. Therefore, adherence to the criteria as specified in the protocol is essential.

[0195] Participant Inclusion Criteria

[0196] Each participant must meet all the following criteria to be enrolled in this study:

[0197] 1 . Is capable of understanding the written informed consent form (ICF), has provided signed written informed consent, and agrees to comply with protocol requirements.

[0198] 2. Is male or female at birth, and > 18 years of age and < 81 years of age at Screening.

[0199] 3. Has a diagnosis of Sjogren’s Disease according to 2016 ACR-EULAR Classification Criteria.

[0200] 4. Has ESSDAI value > 5, counting only the biological, hematological, articular, cutaneous, glandular, lymphadenopathy, and constitutional organ domains at Screening.

[0201] 5. Is seropositive at Screening for anti-SSA antibodies tested at a central laboratory.

[0202] 6. Has stimulated whole salivary flow rate at Screening of > 0.1 mL / min.

[0203] 7. Weighs at least 40 kg and no more than 150 kg and has a body mass index (BMI) within the range of 18-40 kg / m2.

[0204] 8. Routine adult vaccinations, including COVID-19, influenza, pneumonia, and zoster, should be up to date and / or vaccines offered at least 2 weeks prior to randomization according to regional and national guidelines based on medical history or presence of risk factors, in the opinion of the Investigator.

[0205] 9. If applicable (i.e., home dosing permitted by local regulations), participant has appropriate home storage (refrigerated 2°C-8°C) for study drug.

[0206] 10. If female, must be either postmenopausal (defined as no menses for 12 months without other medical cause), permanently surgically sterile (i.e., removal of ovaries, fallopian tubes, and / or uterus), or, for women of childbearing potential, must: a. Be nonpregnant, nonlactating, and agree to remain abstinent or use a method of contraception with a failure rate of < 1 % per year from the screening visit until 30 days after EOS visit. Examples of contraception methods with a failure rate of < 1% per year include: i. hormonal contraceptives associated with inhibition of ovulation (stable dose for at least 4 weeks prior to first dose of study drug); Hormonal contraceptive methods must be supplemented by a barrier method ii. hormone-releasing or copper intrauterine device

[0207] Hi. other intrauterine system iv. bilateral tubal occlusion v. vasectomized male partner vi. abstinence from heterosexual intercourse; the reliability of sexual abstinence should be evaluated based on duration of the study and usual lifestyle of the participant. Intermittent abstinence (such as calendar, ovulation, symptothermal or postovulation) and withdrawal are not considered acceptable contraceptive methods b. The definition of childbearing potential may be adapted for alignment with local guidelines or regulations

[0208] 11 . Sexually active male participants must have documented vasectomy or must agree to use a condom or method of contraception with a failure rate of <1% per year, as defined above with their partners of childbearing potential from first dose of study drug until 30 days after the last study drug administration.

[0209] 12. Male participants must agree to refrain from donating sperm from first dose of study drug until 30 days after the last study drug administration. Female participants must agree to refrain from donating eggs from first dose of study drug until 30 days after the end of study visit.

[0210] 13. Females of childbearing potential must have a negative serum p-human chorionic gonadotropin test during screening and negative urine pregnancy test on Day 1 .

[0211] Participant Exclusion Criteria

[0212] Participants meeting any of the following criteria will be excluded from the study:

[0213] 1 . Prior exposure to any other anti-CD40 / CD154 agent.

[0214] 2. Diagnosis of Sjogren's Disease overlap syndromes where another autoimmune rheumatic disease constitutes the principal illness, including fibromyalgia with currently active, inadequately controlled symptoms.

[0215] 3. Is currently enrolled in another clinical study (at the time of Screening), with the exception of observational studies.

[0216] 4. Has received agents that deplete B or T cells (e.g., rituximab, alemtuzumab) within 1 year prior to Screening.

[0217] 5. Has received treatment with any of the following in the 6 months prior to Screening: a. Anti-BAFF mAb b. CTLA4-Fc IG (abatacept) c. Anti-TNF-a mAb d. Intravenous IG e. Plasmapheresis f. Intravenous or oral cyclophosphamide g. Cataract surgery, Lasik, or other ophthalmologic surgery procedure (e.g., lachrymal plug)

[0218] 6. Injectable corticosteroids (including intra-articular) or treatment with > 10 mg / day dose oral prednisone or equivalent within 8 weeks prior to randomization. (Note: Concomitant treatment with nonsteroidal anti-inflammatory drugs, acetaminophen, oral corticosteroids [equivalent to prednisone < 10 mg / day], or inhaled corticosteroids at a stable dose > 4 weeks prior to baseline for stable medical conditions is allowed and should be kept at a stable dose throughout the study).

[0219] 7. Has started, stopped or adjusted dose / regimen of medications for treatment of, or known to cause, dry mouth / eyes (such as sialagogues, artificial saliva, artificial tears, other topical ophthalmologic agents, antihistamines, antidepressants, anticholinergics, sedatives, antipsychotic drugs, or anti-Parkinson agents), within the 30 days prior to screening or is anticipating change to these treatment regimens during the study.

[0220] 8. Has history of immunodeficiency (e.g., immune disorders or disorders that result in decreased immunity), including human immunodeficiency virus (HIV). HIV test will be performed during screening unless participant has a previously documented negative HIV result within 8 weeks prior to Screening.

[0221] 9. Positive (or 2 indeterminate) QuantiFERON® test results unless confirmation of prior completion of appropriate treatment for latent TB and no evidence of active TB

[0222] - QuantiFERON TB-Gold (QFT) testing should be performed through the central laboratory. QFT testing may be performed by a local laboratory with approval from the medical monitor. QFT test will be performed during screening unless participant has a previously documented negative QFT result within 8 weeks prior to Screening or documented prior positive QFT at any time.

[0223] - An indeterminate QFT test should be repeated.

[0224] - A positive QFT test or two successive indeterminate QFT results should be considered a positive diagnostic TB test.

[0225] - An indeterminate QFT test followed by a negative QFT test should be considered a negative diagnostic TB test.

[0226] - When possible, QFT test should be performed at least 4 weeks after receiving an mRNA COVID-19 vaccine.

[0227] 10. Has received immunization with a live (attenuated) vaccine within 4 weeks prior to randomization or is expected to receive live (attenuated) vaccine during the study or within 6 weeks after the last study drug administration.

[0228] 11 . Has a history of positive or intermediate results for hepatitis C virus infection or chronic active hepatitis B infection (at Screening) as defined below: a. Hepatitis C antigen positive b. Hepatitis B surface antigen positive c. Hepatitis B anti-core antibody positive but anti-surface antibody negative.

[0229] 12. Has any prior history of lymphoid malignancy associated with Sjogren’s Disease diagnosis. 13. Has any history of malignancy (not associated with Sjogren’s Disease) within the last 5 years from Screening, except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured.

[0230] 14. Has a known high risk of infection (e.g., history of hereditary or acquired immune deficiency disorder), a history of an infected joint prosthesis at any time with that prosthesis still in situ, leg ulcers, indwelling urinary catheter.

[0231] 15. Has a history of chronic or recurrent infectious disease, including, but not limited to, chronic renal infection, chronic chest infection, sinusitis, recurrent urinary tract infection (within a month prior to Screening), or an open, draining infected skin wound.

[0232] 16. Has any known or suspected active infection, or has had a serious infection requiring hospitalization, or has been treated with IV / IM antibiotics for an infection within 8 weeks prior to first dose of study drug or treatment with oral antibiotics for an infection within 2 weeks prior to first dose of study drug.

[0233] 17. Laboratory values meeting the following criteria within the screening period (prior to randomization) of study drug: a. Serum aspartate aminotransferase > 3 x upper limit of normal (ULN); b. Serum alanine aminotransferase > 3 x ULN; c. Total bilirubin > 2 x ULN (with the exception of Gilbert’s syndrome); d. Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease formula < 40 mL / min / 1 .73 m2; e. Absolute neutrophil count < 500 / pL; f. Hemoglobin < 8 g / dL; g. Total white blood cell count < 1 ,000 / pL; h. Platelet count < 70,000 / pL; i. Absolute lymphocyte count < 500 / pL

[0234] NOTE: Because Sjogren’s Disease patients are prone to cytopenia, clinical laboratory values in the hematologic domain are appropriately adjusted.

[0235] 18. History of clinically significant (per Investigator's judgment) drug or alcohol abuse within the last 6 months.

[0236] 19. Has a known hypersensitivity to KPL-404 or to any of its excipients.

[0237] 20. Has received an investigational drug during the 30 days (or 5 half-lives, whichever is longer) before first dose of study drug or is planning to receive an investigational drug (other than that administered during this study) or use an investigational device at any time during the study.

[0238] 21. History of any of the following cardiovascular conditions: a. Moderate to severe congestive heart failure (New York Heart Association Class III or IV); b. Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting; c. Uncontrolled hypertension as defined by confirmed systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.

[0239] 22. Has severe, chronic lung disease requiring continuous home oxygen (O2) administration. 23. Clinically relevant or significant electrocardiogram (ECG) abnormalities, including ECG with QT interval corrected for heart rate (QTc) > 500 msec.

[0240] 24. Any condition that, in the opinion of the Investigator, could interfere with evaluation of the study drug or interpretation of participant safety or confound the results of the study.

[0241] 25. Pregnant or breastfeeding or intending to become pregnant or father a child during the study or within 6 weeks of the last dose of study drug.

[0242] TREATMENT OF PARTICIPANTS

[0243] Description of Study Drug

[0244] KPL-404 drug product is a monoclonal antibody consisting of 2 heavy chains and 2 light chains covalently linked by disulfide bridges. It binds to CD40 with an affinity of 7.2 nM and blocks activation of B-cells mediated by the CD40-CD154 costimulatory interaction. KPL-404 drug product is supplied at 200 mg / mL concentrations in a sterile preservative-free solution for parenteral administration.

[0245] Placebo is a sterile preservative-free solution with identical composition as the drug product, but without the antibody protein. It is supplied as a single-use vial.

[0246] Table 3: Investigational Medicinal Products

[0247] Abbreviations: SC = subcutaneous.

[0248] Treatments Administered

[0249] In Part A the study windows will be counted from the Baseline Visit. Study drug administration will be performed every 2 weeks (every 14 ± 2 days).

[0250] In Part B the study windows will be counted from the Week 24 Visit. Study drug administration will be performed once every 2 weeks (every 14 ± 2 days). Treatment Administration by Study Period

[0251] KPL-404 drug product and placebo will be administered by SC injection q2wk in Part A of the study through Week 22 and q2wk in Part B, starting at Week 24 through Week 46. Treatment administration in Part A and Part B will occur on-site or remotely, per the Schedule of Activities (SoA).

[0252] Study Drug Administration

[0253] At the Baseline Visit, all participants will be given a loading dose consisting of 2 SC injections. The first study drug injection will be administered at the study site by study site staff. The second study drug injection may be prepared and administered at the study site by the participant or the participant’s caregiver after adequate training and under the supervision of study site personnel.

[0254] In order to improve participant access, reduce participant burden, and increase participant diversity, all other administrations of study drug will be q2wk and may occur at either the study site or remotely, per the SoA. Study drug doses may be self-administered by the participant or administered to the participant by a caregiver at designated visits once the participant or caregiver has been adequately trained by the study site and is proficient at study drug dose preparation and SC administration. Study drug vials will be dispensed to the participant / participant’s caregiver during on-site visit to take home for treatment between the clinic site visits. As permitted by local regulations and site policy, study drug may also be administered to the participant by a visiting home health provider.

[0255] There is no restriction on fasting, water intake, or postures pre- / post dose.

[0256] Study drug (KPL-404 or placebo) should be administered as scheduled within the protocol specified time window. However, provided that sequential administration of study drug doses can be separated by at least 24 hours, missed doses of study drug should be administered as soon as possible, and as long as possible before administration of the next scheduled dose. While an out-of- window administration of study drug represents a protocol deviation, out of window administration is preferable to a missed dose.

[0257] Randomization

[0258] At the Baseline Visit for Part A, participants will be randomly assigned in a double-blind manner to receive subcutaneous administration of one of two KPL-404 dose frequencies (400 mg q2wk or 400 mg q4wk) or matching placebo q2wk using a 1 :1 :1 allocation ratio. Participants allocated to placebo will also be randomized 1 :1 at the Baseline Visit to either KPL-404 400 mg q2wk or KPL- 404 400 mg q4wk for Part B. Participants who were randomized to receive KPL-404 in Part A will receive the same dose level and frequency in Part B.

[0259] Generally, the randomization ratio is 1 :1 :1 (KPL-404400 mg q2wk: KPL-404400 mg q4wk: placebo); however, randomization at Baseline will utilize 4 arms to account for re-allocation of placebo participants prior to the start of Part B. The 4 arms include KPL-404400 mg q2wk; KPL-404400 mg q4wk; placebo for Part A, then KPL-404400 q2wk; and placebo for Part A, then KPL-404 400 mg q4wk. Blinding

[0260] This is a randomized, double-blind study. Part A will be the double-blind placebo-controlled parallel-design efficacy period. Part B will be the active treatment extension period, blinded only to treatment frequency (q2wk or q4wk).

[0261] During the double-blinded period, neither the participant nor any of the Investigator / site staff, the CRO, or Sponsor staff who are involved in the treatment or clinical evaluation of the participants will be aware of the KPL-404 dose level received. The unblinded treatment assignment for each individual participant may be made available to the investigator through the IRT system only in the event of a medical emergency or an adverse reaction that necessitates identification of the study drug for the medical management or welfare of that participant.

[0262] If the treatment allocation for a participant in Part A becomes known to the Investigator or other study staff involved in the management of study participants, the Sponsor and CRO must be notified immediately.

[0263] STUDY DRUG MATERIALS AND MANAGEMENT

[0264] Study Drug

[0265] KPL-404 drug product is a monoclonal antibody consisting of 2 heavy chains and 2 light chains covalently linked by disulfide bridges. It binds to CD40 with an affinity of 7.2 nM, and blocks CD154-mediated activation of B-cells.

[0266] Study Drug Storage

[0267] KPL-404 drug product and placebo should be stored at 2° to 8°C.

[0268] Details on stability and additional details on drug storage can be found in the Pharmacy Manual or a separate written procedure.

[0269] STUDY ASSESSMENTS AND PROCEDURES

[0270] Order of Assessments

[0271] The following assessments should be conducted in the order below, as required, at pre-dose and post-dose time points. Assessments not listed below can be done in any order:

[0272] 1 . Vital signs, patient-reported outcomes, clinician and disease activity assessments

[0273] 2. Blood sampling for safety, PK, efficacy, and biomarker assessments

[0274] 3. Study drug administration (if applicable)

[0275] 4. Observational period: participants will be observed for 60 minutes after dosing at Baseline (Day 1) and Week 24 Visits (first active treatment dose) and 30 minutes after all other dose administrations performed in clinic.

[0276] 5.

[0277] Efficacy Assessments

[0278] Efficacy assessments to be performed at study visits are summarized below. EULAR Sjogren's Syndrome (SS) Disease Activity Index (ESSDAI)

[0279] The ESSDAI will be performed per Schedule of Assessments to measure disease activity of patients with Sjogren's Disease. The clinical assessment will be used to evaluate participants for eligibility, baseline and changes in disease activity. The tool evaluates disease activity across 12 organ systems, or domains, (cutaneous, respiratory, renal, articular, muscular, peripheral nervous system (PNS), central nervous system (CNS), hematological, glandular, constitutional, lymphadenopathy / lymphoma, and biological).

[0280] For purposes of eligibility determination, the following 7 domains will be used: biological, hematological, articular, cutaneous, glandular, lymphadenopathy, and constitutional organ domains. For all other assessments (baseline and subsequent visits) all 12 domains will be used. The clinical tool is meant to capture signs / symptoms related to Sjogren's Disease and not underlying or associated diseases and excludes scoring of permanent organ system damage. ESSDAI administration guidance and an evaluation worksheet for documenting ESSDAI assessments are included in the study manual.

[0281] The investigator should calculate and enter the total clinESSDAI score and instruction for calculation will be given as follows: eCRF completion: Activity level for each Domain to be entered using drop down lists. Calculate and enter the domain level as well as the Total ESSDAI Score e.g. Glandular activity level = 2 (moderate) x ESSDAI weight of 2 = 4. This same calculation should be performed for each domain and the total of all domain scores added.

[0282] Table 4: ESSDAI Scores The Candidate STAR composite score defines participants as systemic activity responders if ESSDAI scores decrease > 3 (compared to baseline).

[0283] Sjogren’s Tool for Assessing Response (STAR)

[0284] The STAR will be used to assess efficacy of KPL-404 in Sjogren's Disease patients at Week 24. The composite measure contains 5 domains:

[0285] • Systemic activity: 3 points (clinESSDAI decrease of > 3 points)

[0286] • Patient-reported outcome: 3 points (ESSPRI decrease of at least 1 point or > 15% and Symptoms of dryness, pain, and fatigue rated on 3 numeric rating scales)

[0287] • Lacrimal gland function (assessed by Schirmer’s test or OSS): 1 point

[0288] • Salivary gland function: 1 point (UWSF, SGUS)

[0289] • Biological (assessed by IgG or RF): 1 point (IgG: > 10% reduction and RF: > 25% decrease)

[0290] Unstimulated Salivary Flow

[0291] Unstimulated salivary flow exams will be performed at the baseline visit and applicable inclinic visits, per Schedule of Assessments, to evaluate salivary gland function. For more details please refer to the Study Manual. The Candidate STAR composite score defines participants as domain responders if either their unstimulated salivary increases by 25% (compared to baseline) or increases any amount if no saliva was produced at baseline.

[0292] Stimulated Salivary Flow

[0293] A stimulated salivary flow exam will be performed at screening to evaluate salivary gland function and determine participant eligibility for study participation. Additional stimulated salivary flow exams will be performed throughout the study.

[0294] Schirmer’s Test

[0295] Schirmer’s test will be performed per Schedule of Assessments to evaluate lacrimal gland function. Following a 12-hour washout of cholinergic treatment and artificial tear solutions / lubricants, two sterile Schirmer’s strips will be bent / notched to sit under the participants’ lower eyelids (one strip for each eye, right and left). The participants will gently close their eyes for five minutes before the strips are removed. The strips should be measured from the bent / notched point for the length of the moistened area (in millimeters). Baseline Schirmer’s scores below 5 mm indicate abnormal tear production (dry eyes) whereas scores of 10 mm or higher indicate normal tear production. The Candidate STAR composite score defines participants as lacrimal gland function domain responders if Schirmer’s score is abnormal at baseline and increases 5mm or more or if Schirmer’s score is normal at baseline and does not change to abnormal.

[0296] EULAR Sjogren's Syndrome (SS) Patient Reported Index (ESSPRI)

[0297] The ESSPRI questionnaire is a patient reported outcome that will be collected per Schedule of Assessments to assess changes in participants’ Sjogren’s Disease symptoms. The self-evaluation is comprised of three questions that require participants to rate the severity of their Sjogren’s Disease related symptoms in the areas of dryness, fatigue and pain (joint or muscular). The questionnaire uses a two-week recall period and utilizes a numerical rating scale where an area score of 0 represents no symptoms and a score of 10 represents the most severe symptoms. An overall ESSPRI score is taken by averaging the scores across all three domains. An average score <5 implies low disease activity, and average scores > 5 implies high disease activity. The Candidate STAR composite score defines participants as domain responders if their overall ESSPRI score decreases by > 1 point or > 15%.

[0298] EQ-5D-5L

[0299] The EQ-5D-5L is a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life that can be used in a wide range of health conditions and treatments. The EQ-5D-5L will be collected as described herein. The EQ-5D-5L consists of a descriptive system and the EQ visual analog scale (VAS). The descriptive system comprises 5 dimensions: mobility, self- care, usual activities, pain / discomfort and anxiety / depression. The rating scale records the participant’s self-rated health on a vertical VAS. This can be used as a quantitative measure of health outcome that reflects the participant’s own judgement. The scores on these 5 dimensions can be presented as a health profile or can be converted to a single summary index number (utility) reflecting preferability compared to other health profiles.

[0300] FACIT-Fatigue

[0301] The PROMIS SF v1.0 Fatigue 13a (FACIT-Fatigue) scale assesses fatigue and its impact on patient’s everyday lives, with a 7-day recall. It comprises 13 items, divided into 2 domains: experience (items 1 , 2, 3, 4, and 7), and impacts (other items). Responses of each of the items uses a 5-point Likert Scale from 0 (Not at all) to 4 (Very much). Its content has been validated in patients with Primary Sjogren's Syndrome (pSS). Total score ranges from 0-52, with high scores indicating less fatigue. It has been validated (reliability, construct validity, and ability to detect changes) in cancer patients with anemia. Minimal clinically important difference (MCID) was estimated as 3-point change in anemic cancer patients. No evidence of MCID in pSS patients was found.

[0302] Evaluator Global Assessment

[0303] Evaluator Global Assessment (EGA) is a tool that measures the physician / evaluators global assessment of a participants disease activity and its change from baseline.

[0304] The EGA of disease activity is a 1-item questionnaire that asks clinician to provide the assessment of their patients’ disease activity on a 4-point scale at the time of the consultation. Response choices are: 1 = “not active”, 2 = “mildly active”, 3 = “moderately active”, 4 = “highly active”.

[0305] The Evaluator Global Assessment of Change (EGAC) of disease activity is a 1-item questionnaire that asks the clinician to provide the overall change in their patients’ disease activity on a 7-point scale, compared to just before participant started taking the IMP. Response choices are: 0 = “Very much better”, 1 = “Moderately better”, 2 = “A little better”, 3 = “No change”, 4 = “A little worse”, 5 = “Moderately worse”, 6 = “Very much worse”.

[0306] Patients Global Impression of Symptom Severity

[0307] The Patient Global Impression of Severity (PGIS) of Sjogren's Disease symptom severity is a 1-item questionnaire that asks participants to provide the self-assessment of their overall symptom severity on a 4-point scale for the past week. Response choices are: 1 = “none”, 2 = “Mild”, 3 = “Moderate”, 4 = “Severe”.

[0308] The Patient Global Impression of Change (PGIC) of symptom severity is a 1-item questionnaire that asks the participant to provide the self-assessment of change in their overall Sjogren's Disease symptom severity on a 7-point scale, compared to just before participant started taking the IMP. Response choices are: 0 = “Very much better”, 1 = “Moderately better”, 2 = “A little better”, 3 = “No change”, 4 = “A little worse”, 5 = “Moderately worse”, 6 = “Very much worse”.

[0309] Sjogren’s Syndrome Symptom Diary

[0310] Sjogren’s Syndrome Symptom Diary (SSSD) is a novel patient-reported outcome (PRO) instrument in the form of a daily diary, being developed in line with regulatory guidance. SSSD assesses the severity of eye, mouth, skin dryness, and genital dryness (females only), fatigue, and muscle / joint pain over the past 24 h on a numerical rating scale (NRS) ranging from 0 (no symptom) to 10 (worst possible symptom).

[0311] Salivary Gland Biopsy (optional substudy)

[0312] A salivary gland biopsy will be obtained at baseline, Week 24 and Week 48 in a subset of participants providing consent for the optional substudy. The substudy is designed to provide exploratory biomarker readouts related to glandular changes.

[0313] Salivary Gland Ultrasound (optional substudy)

[0314] A salivary gland ultrasound will be obtained at baseline, Week 24 and Week 48 in a subset of participants providing consent for the optional substudy. The substudy is designed to provide exploratory biomarker readouts related to glandular changes.

[0315] Ocular Staining (optional substudy)

[0316] Ocular staining will be performed at baseline, Week 24 and Week 48 in a subset of participants providing consent for the optional substudy. The substudy is designed to provide exploratory biomarker readouts related to ocular changes.

[0317] Safety Assessments

[0318] Safety assessments to be performed at study visits include the following: assessment of AEs, physical examinations (full and abbreviated) including vital signs measurements, and clinical laboratory tests (hematology, chemistry, urinalysis). Physical Examination

[0319] A full physical examination should include at minimum an evaluation of vital signs, head, eyes, ears, nose, and throat as well as cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. The decision to perform examination of the genitourinary system should be guided by clinical judgement. Body weight and height will be measured and will be recorded in the eCRF. Any abnormality identified at baseline should be recorded on the medical history and physical examination eCRFs. At selected visits as specified, an abbreviated physical examination will be performed to evaluate vital signs, lung, and heart sounds.

[0320] At all visits at the study site, limited symptom directed physical examinations may need to be performed to determine changes from baseline or abnormalities and should be recorded in the source documentation. New or worsened abnormalities should be recorded as AEs on the Adverse Event eCRF.

[0321] Vital Signs

[0322] Vital signs include measurements of respiratory rate, heart rate, systolic and diastolic blood pressure, temperature, and pulse oximetry. Blood pressure measurements should be obtained after the participant has been seated for at least 5 minutes.

[0323] Electrocardiogram

[0324] Electrocardiogram (ECG) will be performed as per standard of care (e.g., after participant has been resting in supine position for 5 minutes). The ECG must include the following measurements: heart rate, QRS, QT, QTc, and PR intervals.

[0325] Chest X-ray

[0326] A chest X-ray, 2 views (posterior-anterior and lateral or oblique view), will be performed as part of a general baseline screen for underlying pulmonary disease. The chest x-ray will not be required if a participant had a previously documented normal chest x-ray within 120 days of screening.

[0327] Clinical Safety Laboratory Tests

[0328] Any abnormal laboratory test results (hematology, chemistry, or urinalysis) or other safety assessments (e.g., physical examination, vital signs measurements), including those that worsen from baseline and are believed to be clinically significant in the medical and scientific judgement of the Investigator are to be recorded as AEs or SAEs.

[0329] Laboratory assessments will be performed at study visits as summarized herein. Unscheduled laboratory assessments for safety issues are permitted as deemed necessary by the Investigator. Hematology

[0330] Hematology tests performed at the central study laboratory include white blood cell count with differential, platelet count, red blood cell count, mean corpuscular volume, hemoglobin, and mean corpuscular hemoglobin concentration.

[0331] Chemistry

[0332] Blood chemistry tests performed at the central study laboratory include albumin, total protein, alkaline phosphatase, ALT / SGPT, AST / SGOT, direct bilirubin, total bilirubin, bicarbonate, chloride, potassium, sodium, creatinine, glucose, and lipase.

[0333] Urinalysis

[0334] Urinalysis performed by the central study laboratory includes specific gravity, pH, protein, urobilinogen, ketones, glucose, blood, bilirubin, nitrites, and leukocyte esterase.

[0335] Pregnancy Test

[0336] For women of childbearing potential, a serum pregnancy test will be performed at screening. Participants with positive or indeterminate pregnancy test during the screening are not eligible for the study.

[0337] At subsequent study visits, a urine pregnancy test using a licensed test (dipstick) should be performed. Additional pregnancy tests (serum or urine) may be performed as needed during the study or according to national guidelines.

[0338] A urine pregnancy test must be performed 6 weeks after the last study drug administration. The purpose of pregnancy testing is to prevent, identify, and / or minimize embryo / fetal exposure to study drug.

[0339] STATISTICAL AND ANALYTICAL PLAN

[0340] Primary Efficacy Endpoint

[0341] The primary efficacy endpoint is change from baseline in EULAR Sjogren’s Disease Activity Index (ESSDAI) at Week 24.

[0342] Key Secondary Efficacy Endpoint

[0343] • Proportion of Sjogren’s Tool for Assessing Response (STAR) Responders (> 5 points) at Week 24 and evaluation of the individual STAR domains

[0344] Other Secondary Efficacy Endpoints

[0345] • Change from baseline in Stimulated Salivary Flow at Week 24

[0346] • Change from baseline in FACIT-Fatigue

[0347] • Change from baseline in EQ-5DL

[0348] Safety / PK / PD Endpoints

[0349] • Incidence of Treatment-emergent adverse events (TEAEs), and serious AEs (SAEs) • Clinically significant laboratory or ECG changes

[0350] • KPL-404 plasma concentrations over time, PK parameters

[0351] • Antidrug antibodies

[0352] • Receptor occupancy (RO; US clinical sites only)

[0353] Exploratory Endpoints

[0354] • Proportion of patients achieving >3 points reduction (minimal clinically important improvement) from baseline in ESSDAI score at Week 24

[0355] • Proportion of patients achieving "low systemic disease activity" defined as ESSDAI <5 at Week 24

[0356] • Change from baseline in Evaluator Global Assessment of Disease Activity (EGA) and change in disease activity (EGAC) at Week 24

[0357] • Change from baseline in Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) at Week 24

[0358] • Change from baseline in Sjogren’s Syndrome Symptom Diary (SSSD)

[0359] • Change from baseline in ocular surface staining score (optional sub-study)

[0360] • Changes in histology (including focus score), immunohistochemistry biomarkers and spatial transcriptomic and proteomic profiles in salivary gland biopsies at Week 24 (optional sub-study)

[0361] • Changes in salivary gland ultrasound score at Week 24 using the Hocevar scale (optional sub-study)

[0362] • Changes from baseline in systemic cytokines and chemokines including CXCL13, B cell activating factor (BAFF) CRP and type 1 interferons

[0363] • Changes from baseline in systemic complement factors (including CH50, C3 and C4)

[0364] • Changes from baseline in RF, anti-SSA, anti-SSB, total IgG

[0365] • Changes from baseline in lymphocyte populations including b-cell populations

[0366] Sample Size Calculations

[0367] Approximately 200 participants will be enrolled into the randomized, double-blind, placebo- controlled period (Part A) with approximately 67 participants assigned to each of the 3 treatment arms.

[0368] The primary efficacy endpoint is the change from baseline in ESSDAI at Week 24. The sample size is based on a 2-sample t-test assuming an improvement in ESSDAI change from baseline for the KPL-404 being 2.0 points better than placebo (improvement for placebo = 4.5 point, standard deviation = 3.6) at Week 24 in Part A. Enrollment of 60 participants in each of the 3 treatment arms (KPL-404 400 mg q2wk, KPL404 400 mg q4wk, and placebo) allows 85% power for the treatment comparison with 2-sided 0.05 type 1 error if all participants complete 24 weeks of ESSDAI assessments. In order to account for an anticipated discontinuation rate of 10%, up to 67 participants per arm and for a total of up to 201 participants are required to enroll under Part A. The power to detect the treatment difference of 27% at a 2-sided alpha level of 0.05 for the key secondary efficacy endpoint (i.e., change from baseline in Sjogren’s Tool for Assessing Response [STAR] at Week 24) is 85% with the assumptions of placebo response rate 34% and KPL-404 response rate 61%.

[0369] The sample size calculation was performed using SAS 9.4 power procedure.

[0370] Analysis Populations

[0371] The following analysis populations will be used in the statistical analyses:

[0372] Modified Intent-to-Treat (mITT) Analysis Population includes all randomized participants who receive at least one dose of KPL-404 or placebo and have at least 1 post-baseline assessment in ESSDAI during the double-blind Treatment Period Part A. The primary analysis for efficacy endpoints will be based on the mITT population. Treatment comparisons for all mITT analyses will be based on each participant’s treatment assignment from randomization.

[0373] Safety Population includes all participants who received at least one dose of study drug. Safety analyses will be based on the actual treatment a participant received.

[0374] Per Protocol (PP) Population includes all mITT participants who have no important protocol deviations that may potentially bias efficacy analyses of the study. This analysis population may be used for sensitivity analyses for selected efficacy endpoints.

[0375] Pharmacokinetic (PK) Population includes participants who receive at least 1 dose of study drug and have at least 1 PK sample. The PK population will be used for all PK analyses.

[0376] Statistical Analysis Methodology

[0377] General Methods

[0378] All statistical analyses will be performed using SAS® Version 9.4 or higher. Descriptive statistics will be presented for all endpoints and will include number of participants (n), mean, standard deviation, median, interquartile range, minimum and maximum for continuous variables, and frequency and percentage for categorical and ordinal variables.

[0379] Estimands

[0380] The primary estimand defined for the primary endpoint is summarized in Table 5. Table 5: Summary of Primary Estimand for Primary Endpoint. Stratified Analysis

[0381] Randomization will not be stratified.

[0382] Testing Hypotheses and Multiplicity Adjustment

[0383] The statistical hypotheses for comparing each KPL-404 dose group to placebo on the primary endpoint are as follows:

[0384] • HO: No treatment difference between KPL-404 and placebo.

[0385] • H1 : There is a treatment difference between KPL-404 and placebo. No multiplicity adjustment will be made in this Phase 2 study.

[0386] Analysis of Primary Efficacy Endpoint

[0387] The primary estimand for the primary endpoint is defined in Table 5, using the treatment policy / hypothetical strategies. Off-study treatment data up to Week 24 will be included in the analysis. Data will be set to missing values after prohibited / rescue medication that potentially impact efficacy analyses prior to Week 24, and the participant’s worst post baseline observation before the time of the medication usage will be carried forward (WOCF) to impute missing endpoint value (for participants whose postbaseline values are all missing, the baseline will be used to impute). Missing data at Week 24 will be imputed with Multiple Imputation (Ml) method. This Ml method will use participants excluding those who used prohibited / rescue medications that potentially impact efficacy analyses prior to Week 24 and excluding participants who discontinue due to lack of efficacy prior to Week 24 as input.

[0388] Each of the imputed complete data will be analyzed by fitting an analysis of covariance (ANCOVA) model with treatment as a fixed effect factor, baseline as covariate. The number of imputed datasets will be about 40. Statistical inference obtained from all imputed data will be combined using Rubin’s rule. Descriptive statistics including number of participants, mean, standard error, and least squares (LS) mean percent changes (and standard error) will be provided. In addition, difference of each KPL-404 dose group against placebo in LS means and the corresponding 95% Cl) will be provided along with the p-values.

[0389] Analysis of Secondary Efficacy Endpoints

[0390] For binary efficacy endpoint, off-study treatment data up to Week 24 will be included in the analysis, and participants will be considered as non-responders after usage of prohibited / rescue medications that potentially impact efficacy analyses or discontinuing treatment due to lack of efficacy prior to Week 24. Additionally, participants with missing data at Week 24 will be defined as non- responders. The analyses will use Chi-Square test. Response rate difference will be derived. In addition, odds ratio and the corresponding 95% Cl will be provided along with the p-values. For other continue endpoints, the similar analyses to primary endpoint will be performed. Analysis of Exploratory Endpoints

[0391] Analyses similar to secondary endpoints will be performed.

[0392] Analysis of Immunogenicity Pre-dose ADA blood samples will be collected according to the schedule in protocol.

[0393] ADA data will be summarized using descriptive statistics by treatment group. Drug concentration data will be examined and the influence of ADAs on individual concentration-time profiles will be evaluated. Details are in a separate analysis plan. Analysis of Pharmacokinetics

[0394] For all participants, serum samples will be collected at time points shown in the SoA in order to quantify concentrations of KPL-404. Descriptive statistics will be calculated for the serum concentrations of KPL-404 by visit. Individual listings of serum concentrations will be provided.

[0395] Pharmacokinetic data may be used in a subsequent population PK evaluation that will be conducted outside of this study and described in a separate report.

[0396] Table 6: Schedule of Activities: Part A - Randomized, Double-blind, Placebo-controlled Period

[0397]

[0398]

[0399]

[0400] Abbreviations: AE = adverse event, -hCG = beta-human chorionic gonadotropin, COVID-19 = coronavirus disease 2019, ECG = electrocardiogram,

[0401] EGA = Evaluators Global Assessment, EGAC = Evaluators Global Assessment of Change, EOT = end of treatment, HBV = hepatitis B virus, HIV = human immunodeficiency virus, IP = investigational product, PGIC = Patient Global Impression of Change, PGIS = Patient Global Impression of Severity, PRO = patient reported outcome, PT = prothrombin time, PTT = partial thromboplastin time, SSSD = Sjogren’s Syndrome Symptom Diary, WOCBP = women of 5 childbearing potential.

[0402] a. If a participant prematurely discontinues study drug treatment prior to the completion of the treatment period at Week 24 (i.e., end of treatment [EOT]), the procedures for the EOT visit should be conducted within approximately 2 weeks after study drug discontinuation, and the participant should be encouraged to complete the remaining visits. All participants who prematurely discontinue study drug will then enter Part C, the Safety Follow-up Period

[0403] 5 for 8 additional weeks. Participants who complete study drug administration in Part A (through Week 24) and do not continue to Part B will have an EOT Visit-Part A, then enter the Safety Follow-up Period for 8 additional weeks. b. Participants that are not able to administer (self or caregiver) study drug in a remote (i.e., home) setting may have a clinic visit for purposes of study drug administration and other assessments. c. Medical history is to include drug or alcohol abuse within the last 6 months, all Sjogren’s Disease history, cancer within the last 5 years from Screening,

[0404] 10 and all surgical history. d. Prior medications will be recorded up to 60 days prior to Screening. e. Full physical examination includes at minimum evaluation of vital signs, head, eye, ear, nose, and throat as well as cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. The decision to perform examination of genitourinary system should be guided by clinical judgement. f. Abbreviated physical examination includes at minimum evaluation of vital signs, lung, and heart sounds. g. Blood pressure, heart rate, and body temperature should be measured before blood draws are performed. h. Adverse event reporting begins when the participant has provided informed consent. During the Screening Period, only SAEs and protocol-related nonserious AEs will be recorded. i. Not required if the patient has had a chest x-ray within 120 days priorto Screening.

[0405] 20 j. Sjogren’s Syndrome Symptom Diary (SSSD) assesses the severity of eye, mouth, skin dryness, and genital dryness (females only), fatigue, and muscle / joint pain over the past 24 h on a scale ranging from 0 (no symptom) to 10 (worst possible symptom). k. Optional substudy. l. Optional substudy. m. Optional substudy.

[0406] 25 n. All blood draws must be done pre-dose administration at applicable visits.

[0407] o. QuantiFERON TB-Gold (QFT) testing should be performed through the central laboratory. QFT testing may be performed by a local laboratory with approval from the Sponsor. QuantiFERON testing is not required where participant is known to be QuantiFERON positive. Participants known or testing QuantiFERON positive may be enrolled provided there is confirmation of prior completion of appropriate treatment for latent TB and no evidence of active TB.

[0408] 5 p. Biomarker samples, including serum and whole blood for immunophenotyping, will be collected as required for biomarker collection. Refer to the Laboratory Manual for specific collection tubes, sample volume, sample types, and collection processes. q. STAR / ESSDAI related laboratories including RF, IgG, C3 / C4, CH50, clonal component, GFR, and creatine kinase. Per the Laboratory Manual, cryoglobulin testing may be performed at a qualified central laboratory. r. Samples for central laboratory assessment of hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus antibody, and human

[0409] 10 immunodeficiency virus (HIV) test will be collected at screening. Participants who have not had an HBV and HIV test within 8 weeks of screening will be tested. Participants with test results indicating positive HBV or HIV infection will not be eligible for study participation. Additional infection assessments may be completed locally, as needed, and in accordance with national guidelines (for example, where local regulations or institutional practices require Covid rapid antigen testing). s. Hematology labs will include CBC and differential. Chemistry labs require a minimum 8-hour fast; if a participant is unable to fast when necessary, the non-fasting status will be recorded. t. If serum pregnancy test result is borderline, a repeat test is necessary to confirm eligibility. If still borderline > 3 days later, this will be considered documentation of continued lack of a positive result, and the participant can be enrolled into the study. u. If urine pregnancy test is positive, withhold dosing and perform a serum pregnancy test. Pregnant participants must permanently discontinue investigational product.

[0410] 20 v. Study drug administration will be performed once every 2 weeks (q2wk) (i.e., Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22) every 14 ± 2 days. w. Part A KPL-404 doses or placebo at the Baseline, and the Week 2, 4, 8, 12, 16 and 20 Visits will be administered by SC injection at the study site by study site personnel (except for the 2nd baseline loading dose and Week 2 Visit injection administered by the participant or trained caregiver, under site staff supervision as part of SC injection training).

[0411] Table 7: Schedule of Activities: Part B and Part C - Active Treatment Extension and Safety Follow-Up Periods

[0412]

[0413]

[0414] Abbreviations: AE = adverse event, p-hCG = beta-human chorionic gonadotropin, COVID-19 = coronavirus disease 2019, ECG = electrocardiogram, EGA = Evaluators Global Assessment, EGAC = Evaluators Global Assessment of Change, EOT = end of treatment, HBV = hepatitis B virus, HIV = human

[0415] immunodeficiency virus, IP = investigational product, PGIC = Patient Global Impression of Change, PGIS = Ptient Global Impression of Severity, WOCBP = women of childbearing potential. a Participants who prematurely discontinue study drug administration in Part B (at any point after the Week 24 Visit and prior to the Week 48 Visit) will have

[0416] 5 an EOT Visit-Part B within approximately 2 weeks from last dose of study drug, and then enter the Safety Follow-up Period for 8 additional weeks If the participant is unable to complete the EOT Visit-Part B visit in-clinic, the visit may be conducted by telephone and will collect date of the contract and vital status (yes / no) b Participants enter the Safety follow-up Period for 8 weeks from last study drug administration. If the participant misses the safety follow-up visit, effort should be made to contact the participant by telephone and record date of the contact and vital status (yes / no).

[0417] 10 c Abbreviated physical examination includes at minimum evaluation of vital signs, lung, and heart sounds. d. Blood pressure, heart rate, and body temperature should be measured before blood draws are performed. e. Adverse event reporting begins when the participant has provided informed consent. During the Screening Period, only SAEs and protocol-related nonserious AEs will be recorded. f. Sjogren’s Syndrome Symptom Diary (SSSD) assesses the severity of eye, mouth, skin dryness, and genital dryness (females only), fatigue, and muscle / joint pain over the past 24 h on a scale ranging from 0 (no symptom) to 10 (worst possible symptom). g. Optional substudy. h. Optional substudy.

[0418] I. All blood draws must be done pre-dose administration at applicable visits. j. Biomarker samples, including serum and whole blood for immunophenotyping, will be collected as required for biomarker collection. Refer to the

[0419] 20 Laboratory Manual for specific collection tubes, sample volume, sample types, and collection processes. k. STAR / ESSDAI Related Laboratories including RF, IgG, C3 / C4, CH50, Clonal Component, GFR, and Creatine Kinase. Per the Laboratory Manual, cryoglobulin testing may be performed at a qualified central laboratory. l. Hematology labs will include CBC and differential. Chemistry labs require a minimum 8-hour fast; if a participant is unable to fast when necessary, the nonfasting status will be recorded.

[0420] 25 m. If urine pregnancy test is positive, withhold dosing and perform a serum pregnancy test. Pregnant participants must permanently discontinue investigational product.

[0421] n. Study drug administration will be performed once every 2 weeks (q2wk) (i.e., Weeks 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 46) every 14 ± 2 days.

[0422] Participants that are not able to administer (self or caregiver) study drug in a remote (i.e., home) setting may have a clinic visit for purposes of study drug administration and other assessments.

[0423] Table 8: Clinical Laboratory Evaluations

[0424] Abbreviations: ALT = alanine aminotransferase, anti-SSA = anti-Sjbgren's-syndrome-related antigen A autoantibodies, anti-SSB = anti-Sjogren's-syndrome-related antigen B autoantibodies, AST = aspartate aminotransferase, GFR = glomerular filtration rate, GT = glutamyl transferase, HbsAg = hepatitis B surface antigen, HbsAb = hepatitis B surface antibody, HbcAb = hepatitis B core antibody; HCVAb = hepatitis C antibody; HIV = human immunodeficiency virus, IgG = immunoglobulin G, INR = International Normalization Ratio, MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, MCV = mean corpuscular volume, MDMA = methylenedioxymethamphetamine, PT = prothrombin time, PTT = partial thromboplastin time, RF = rheumatoid factor, SSA = Sjogren’s Syndrome-associated Antibody A, SSB = Sjogren’s Syndrome-associated Antibody B. a Per the Laboratory Manual, cryoglobulin testing may be performed at a qualified central laboratory. Table 9: List of Abbreviations and Definitions of Terms

[0425] Example 2. Treatment of a Subject with Sjogren’s Disease

[0426] A subject with Sjogren’s disease undergoes treatment with KPL-404 therapy. The subject receives a subcutaneous 800 mg loading dose of KPL-404 formulated at 200 mg / mL administered with two subcutaneous injections, each injection having a volume of 2 mL, at the onset of treatment. The subject then receives subcutaneous administrations of 400 mg of KPL-404 in a 2 mL injection volume once every four weeks. After three months of treatment, the subject is administered a EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI). The Subjects ESSDAI score is reduced by 4. It is determined that the subject’s condition has not worsened, and the subject continues with the course of treatment by receiving subcutaneous administrations of 400 mg of KPL-404 once every four weeks.

[0427] Example 3. PK Dosage Modeling

[0428] To evaluate dosing for Sjogren’s disease, a population PK model developed using KPL-404 concentration-time data from healthy volunteers in NCT04497662 (A Phase 1 First-in-human Randomized, Double-blind, Placebo-controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Ascending Intravenous and Subcutaneous Doses of KPL-404 in Healthy Subjects) was updated using anonymized PK data from NCT05198310 (A Phase 2, Multicenter, Randomized, Double-blind, Placebo Controlled Study to Assess the Safety, Pharmacokinetics, and Efficacy of KPL-404 in Subjects With Moderate to Severe Active Rheumatoid Arthritis With Inadequate Response or Intolerance to at Least One Biologic Disease-modifying Antirheumatic Drug or a Janus Kinase Inhibitor) Cohorts 1-4 . The model simulated PK profiles for KPL- 404 dose regimens via subcutaneous administration. Results are shown in FIGS. 2A-5B.

[0429] Other Embodiments

[0430] While specific aspects of the invention have been described and illustrated, such aspects should be considered illustrative of the invention only and not as limiting the invention as construed in accordance with the accompanying claims. All publications and patent applications cited in this specification are herein incorporated by reference in their entirety for all purposes as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference for all purposes. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

[0431] Other embodiments are in the claims.

Claims

CLAIMS1. A method of treating Sjogren’s disease in a human subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a humanized anti-CD40 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10.

2. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 100 mg to about 1000 mg.

3. The method of claim 2, wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 400 mg.

4. The method of any one of claims 1-3, wherein the method further comprises administering a loading dose comprising about 100 mg to about 1000 mg of the antibody or antigen-binding fragment thereof.

5. The method of claim 4, wherein the loading dose is about 800 mg.

6. The method of any one of claims 1-5, wherein the method further comprising administering a maintenance dose comprising about 400 mg of the antibody or antigen-binding fragment thereof.

7. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 1 mg / kg to about 20 mg / kg.

8. The method of claim 7, wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 2 mg / kg to about 10 mg / kg.

9. The method of claim 7 or 8, further comprising administering a loading dose comprising about 5 mg / kg to about 20 mg / kg of the antibody or the antigen-binding fragment thereof.

10. The method of any one of claims 7-9, further comprising administering a maintenance dose of the antibody or antigen-binding fragment thereof.11 . The method of any one of claims 1-10, wherein the antibody or antigen binding fragment thereof is administered about once per week, once every two weeks, once every three weeks, or once every four weeks.

12. The method of claim 11 , wherein the antibody or antigen binding fragment thereof is administered about every two weeks.

13. The method of claim 11 , wherein the antibody or antigen binding fragment thereof is administered about once every four weeks.

14. The method of any one of claims 1-13, wherein the pharmaceutical composition is administered intravenously or intrathecally.

15. The method of any one of claims 1-13, wherein the pharmaceutical composition is administered subcutaneously.

16. The method of any one of claims 1-15, wherein the pharmaceutical composition comprises the antibody or antigen-binding fragment thereof at a concentration of from about 50 mg / mL to about 300 mg / mL.

17. The method of claim 16, wherein the pharmaceutical composition comprises the antibody or antigen-binding fragment thereof at a concentration of about 200 mg / mL.

18. The method of any one of claims 1-17, wherein the pharmaceutical composition is administered during a treatment regimen of at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, one year, two years, or longer, or until clinical remission is achieved or a minimum low disease activity is achieved.

19. The method of any one of claims 1-18, wherein the pharmaceutical composition is administered during a treatment regimen of about 12 weeks, 24 weeks, 48 weeks, 52 weeks, 104 weeks, or longer, or until clinical remission is achieved or a minimum low disease activity is achieved.

20. The method of any one of claims 1-19, wherein the method improves, stabilizes or reduces one or more symptoms of Sjogren’s disease in the subject relative to a control.21 . The method of any one of claims 1 -20, wherein the subject is 18 to 81 years of age.

22. The method of any one of claims 1-21 , wherein the subject has a EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score that decreases by at least 3 following administration of the composition.

23. The method of any one of claims 1-21 , wherein the subject has an ESSDAI score less than 5 following administration of the composition.

24. The method of any one of claims 1-23, wherein the subject has a Sjogren’s Tool for AssessingResponse (STAR) score of > 5 following administration of the composition.

25. The method of any one of claims 1 -24, wherein the subject has an increase of at least 25% in unstimulated salivary flow following administration of the composition or, alternatively, an increase in unstimulated salivary flow following administration of the composition if no saliva was produced prior to administration of the composition.

26. The method of any one of claims 1-25, wherein the subject has an improvement in stimulated salivary flow following administration of the composition.

27. The method of any one of claims 1-26, wherein the subject has a Schrimer’s test score of 10 mm or higher following administration of the composition.

28. The method of any one of claims 1-26, wherein the subject has an increase of 5 mm in Schrimer’s test score following administration of the composition if Schrimer’s test score was below 5 mm prior to administration of the composition or, alternatively, Schrimer’s test score > 5 mm following administration of the composition if Schrimer’s test score is 10 mm or higher prior to administration of the composition.

29. The method of any one of claims 1-28, wherein the subject has a decrease in a EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) score of at least 1 or at least 15% following administration of the composition.

30. The method of any one of claims 1-29, wherein the subject has an improvement in a EuroQol 5 Dimension 5 Level (EQ-5D-5L) score following administration of the composition.

31. The method of any one of claims 1-30, wherein the subject has an increase in a Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) score following administration of the composition.

32. The method of any one of claims 1 -31 , wherein the subject has an Evaluator Global Assessment (EGA) score of 3 or less following administration of the composition.

33. The method of any one of claims 1 -31 , wherein the subject has an improvement in EGA score following administration of the composition.

34. The method of any one of claims 1-33, wherein the subject has an Evaluator Global Assessment of Change (EGAC) score of 0 to 2 following administration of the composition.

35. The method of any one of claims 1-34, wherein the subject has a Patient Global Impression of Severity (PGIS) score of 3 or less following administration of the composition.

36. The method of any one of claims 1-35, wherein the subject has a Patient Global Impression of Change (PGIC) score of 0 to 2 following administration of the composition.

37. A method of immunosuppression in a human subject with Sjogren’s disease comprising administering to the subject a pharmaceutical composition comprising a humanized anti-CD40 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10.

38. The method of claim 37, wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 100 mg to about 1000 mg.

39. The method of claim 38, wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 400 mg.

40. The method of any one of claims 37-39, wherein the method further comprises administering a loading dose comprising about 100 mg to about 1000 mg of the antibody or antigen-binding fragment thereof.41 . The method of claim 40, wherein the loading dose is about 800 mg.

42. The method of any one of claims 37-41 wherein the method further comprising administering a maintenance dose comprising about 400 mg of the antibody or antigen-binding fragment thereof.

43. The method of claim 37, wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 1 mg / kg to about 20 mg / kg.

44. The method of claim 43, wherein the antibody or antigen-binding fragment thereof is administered at a dosage of about 2 mg / kg to about 10 mg / kg.

45. The method of claim 43 or 44, further comprising administering a loading dose comprising about 5 mg / kg to about 20 mg / kg of the antibody or the antigen-binding fragment thereof.

46. The method of any one of claims 43-45, further comprising administering a maintenance dose of the antibody or antigen-binding fragment thereof.

47. The method of any one of claims 37-46, wherein the antibody or antigen binding fragment thereof is administered about once per week, once every two weeks, once every three weeks, or once every four weeks.

48. The method of claim 47, wherein the antibody or antigen binding fragment thereof is administered about once every two weeks.

49. The method of claim 47, wherein the antibody or antigen binding fragment thereof is administered about once every four weeks.

50. The method of any one of claims 37-49, wherein the pharmaceutical composition is administered intravenously or intrathecally.

51. The method of any one of claims 37-49, wherein the pharmaceutical composition is administered subcutaneously.

52. The method of any one of claims 37-51 , wherein the pharmaceutical composition comprises the antibody or antigen-binding fragment thereof at a concentration of from about 50 mg / mL to about 300 mg / mL.

53. The method of claim 52, wherein the pharmaceutical composition comprises the antibody or antigen-binding fragment thereof at a concentration of about 200 mg / mL.

54. The method of any one of claims 37-53, wherein the pharmaceutical composition is administered during a treatment regimen of at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, one year, two years, or longer, or until clinical remission is achieved or a minimum low disease activity is achieved.

55. The method of any one of claims 37-54, wherein the pharmaceutical composition is administered during a treatment regimen of about 12 weeks, 24 weeks, 48 weeks, 52 weeks, 104 weeks, or longer, or until clinical remission is achieved or a minimum low disease activity is achieved.

56. The method of any one of claims 37-55, wherein the method improves, stabilizes or reduces one or more symptoms of Sjogren’s disease in the subject relative to a control.

57. The method of any one of claims 37-56, wherein the subject is 18 to 81 years of age.

58. The method of any one of claims 37-57, wherein the subject has a EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score that decreases by at least 3 following administration of the composition.

59. The method of any one of claims 37-57, wherein the subject has an ESSDAI score less than 5 following administration of the composition.

60. The method of any one of claims 37-59, wherein the subject has a Sjogren’s Tool for Assessing Response (STAR) score of > 5 following administration of the composition.61 . The method of any one of claims 37-60, wherein the subject has an increase of at least 25% in unstimulated salivary flow following administration of the composition or, alternatively, an increase in unstimulated salivary flow following administration of the composition if no saliva was produced prior to administration of the composition.

62. The method of any one of claims 37-61 , wherein the subject has an improvement in stimulated salivary flow following administration of the composition.

63. The method of any one of claims 37-62, wherein the subject has a Schrimer’s test score of 10 mm or higher following administration of the composition.

64. The method of any one of claims 37-62, wherein the subject has an increase of 5 mm in Schrimer’s test score following administration of the composition if Schrimer’s test score was below 5 mm prior to administration of the composition or, alternatively, Schrimer’s test score > 5 mm following administration of the composition if Schrimer’s test score is 10 mm or higher prior to administration of the composition.

65. The method of any one of claims 37-64, wherein the subject has a decrease in a EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) score of at least 1 or at least 15% following administration of the composition.

66. The method of any one of claims 37-65, wherein the subject has an improvement in a EuroQol 5 Dimension 5 Level (EQ-5D-5L) score following administration of the composition.

67. The method of any one of claims 37-66, wherein the subject has an increase in a Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) score following administration of the composition.

68. The method of any one of claims 37-67, wherein the subject has an Evaluator Global Assessment (EGA) score of 3 or less following administration of the composition.

69. The method of any one of claims 37-67, wherein the subject has an improvement in EGA score following administration of the composition.

70. The method of any one of claims 37-69, wherein the subject has an Evaluator Global Assessment of Change (EGAC) score of 0 to 2 following administration of the composition.

71. The method of any one of claims 37-70, wherein the subject has a Patient Global Impression of Severity (PGIS) score of 3 or less following administration of the composition.

72. The method of any one of claims 37-71 , wherein the subject has a Patient Global Impression of Change (PGIC) score of 0 to 2 following administration of the composition.

73. The method of any one of claims 1-36, wherein the subject has an IgG decrease of at least 10% or rheumatoid factor (RF) level decrease of at least 25% following administration of the composition.

74. The method of any one of claim 37-72, wherein the subject has an IgG decrease of at least 10% or rheumatoid factor (RF) level decrease of at least 25% following administration of the composition.

75. The method of any one of claims 1-21 and 24-36, wherein the subject has an improvement in EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score following administration of the composition.

76. The method of any one of claims 37-57 and 60-72, wherein the subject has an improvement in EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score following administration of the composition.

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