Methods of treating cancer with Anti-CCR8 / Anti-CD3 bispecific antibodies

Abstract

The present invention relates to the treatment of cell proliferative disorders. More specifically, the invention relates to the specific treatment of human subjects having a solid tumor malignancy using anti-C-C motif chemokine receptor 8 (CCR8) / anti-cluster of differentiation 3 (CD3) bispecific antibodies alone or in combination with an anti-programmed death-ligand 1 (PD-L1) antibody (e.g., atezolizumab).

Description

[0001] METHODS OF TREATING CANCER WITH ANTI-CCR8 / ANTI-CD3 BISPECIFIC ANTIBODIES

[0002] SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 11 , 2025, is named “50474-350WO3_Sequence_Listing_7_11 25” and is 54,263 bytes in size.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to the treatment of cell proliferative disorders. More specifically, the invention relates to the specific treatment of human subjects having a solid tumor malignancy using anti- C-C motif chemokine receptor 8 (CCR8) / anti-cluster of differentiation 3 (CD3) bispecific antibodies alone or in combination with a PD-L1 binding antagonist (e.g., an anti-programmed death-ligand 1 (PD-L1 ) antibody; e.g., atezolizumab).

[0006] BACKGROUND

[0007] Cancer is a leading cause of morbidity and mortality globally and novel treatments are needed. Current treatment options for solid tumor malignancies include chemotherapy, radiation, surgery, targeted therapies, and immunotherapy. One form of immunotherapy, known as checkpoint inhibitor (CPI) therapy, works by blocking inhibitory receptors on T cells, with the goal of enhancing the magnitude and quality of tumor-specific T-cell responses, resulting in anti-tumor activity. PD-L1 is a cell-surface protein that is broadly expressed by tumor cells and tumor-infiltrating immune cells in many human cancers. Overexpression of PD-L1 has been associated with poor prognosis in patients with some cancers. Interruption of the PD-L1 / programmed death-1 (PD-1 ) pathway is an attractive strategy for reinvigorating tumor-specific T-cell immunity. Indeed, multiple inhibitors of PD-L1 or PD-1 have demonstrated clinical efficacy or promising anti-tumor activity in a wide range of tumor types. The clinically observed benefits have led to approvals of multiple anti-PD-L1 (e.g., atezolizumab, avelumab, and durvalumab) and anti- PD-1 antibodies (e.g., nivolumab, pembrolizumab, and cemiplimab-rwlc) in select indications to date. However, not all cancers respond to CPIs, and many tumors progress following initial treatment, suggesting that additional immunosuppressive factors, such as regulatory T (Treg) cells, may be present that inhibit anti-tumor responses. There remains an unmet need for a method of treating cancers that respond poorly to CPIs, such as solid tumors.

[0008] Treg cells constitute a major immunosuppressive cell type in tumors. C-C motif chemokine receptor 8 (CCR8) is a chemokine receptor that is predominantly expressed on activated, proliferating intratumoral Treg cells, which constitute the majority of Treg cells in tumors. In contrast, CCR8 is expressed at a lower level and on a small fraction of Treg-cells in circulation and normal tissues, including the intestine, skin, and lung. Only small fractions of conventional cluster of differentiation (CD) 4+and CD8+effector T cells in tumors express CCR8. The selective expression of CCR8 on intratumoral Treg- cells makes it an attractive candidate for targeted Treg-cell depletion in the tumor context while decreasing the risk for inducing autoimmunity or significant depletion of critical CD8+and CD4+effector T- cells.

[0009] SUMMARY OF THE INVENTION

[0010] The present invention provides methods of treating a subject having a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), cutaneous melanoma, triple-negative breast cancer (TNBC), urothelial carcinoma (UCC), esophageal cancer, gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, clear cell renal cell carcinoma (ccRCC), and hepatocellular carcinoma (HCC), among others) by administering an effective amount of a bispecific antibody that binds CCR8 and CD3 alone or in combination with a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) in a multi-cycle dosing regimen, optionally involving a fractionated, escalating dose of the bispecific antibody in the first dosing cycle.

[0011] In one aspect, the invention features a method of treating a subject having a cell proliferative disorder, comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 0.9 mg (e.g., about 0.1 mg, about 0.45 mg, or about 0.9 mg). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.1 mg, about 0.45 mg, or about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.1 mg, about 0.45 mg, or about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 1 .8 mg, about 100 mg, or about 300 mg.

[0012] In some embodiments, the first dosing cycle is about 21 days. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the first dosing cycle.

[0013] In some embodiments, the dosing regimen comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to six (e.g., one, two, three, four, five, or six) additional dosing cycles. In some embodiments, the dosing regimen comprises one to 20 (e.g., one, two, three, four, five, six, seven, eighteen, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) additional dosing cycles. In some embodiments, the length of each of the one or more additional dosing cycles is about 21 days. In some embodiments, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some embodiments, each single dose of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 1 of the bispecific antibody. In some embodiments, each single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0014] In another aspect, the invention features a method of treating a subject having a cell proliferative disorder, comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher in amount than the Cycle 1 , Dose 1 of the bispecific antibody; and (b) the second dosing cycle comprises a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 0.9 mg (e.g., about 0.1 mg, about 0.45 mg, or about 0.9 mg). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 1 .8 mg, about 100 mg, or about 300 mg. In some embodiments, the Cycle 1 , Dose 2 of the bispecific antibody is about 3 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg.

[0015] In some embodiments, the length of the first dosing cycle is about 21 days. In some embodiments, the Cycle 1 , Dose 1 and the Cycle 1 , Dose 2 of the bispecific antibody are administered to the subject on about Day 1 and about Day 8, respectively, of the first dosing cycle. In some embodiments, the length of the second dosing cycle is about 21 days. In some embodiments, the Cycle 2, Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the second dosing cycle.

[0016] In some embodiments, the dosing regimen comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to six (e.g., one, two, three, four, five, or six) additional dosing cycles. In some embodiments, the dosing regimen comprises one to 20 (e.g., one, two, three, four, five, six, seven, eighteen, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) additional dosing cycles.

[0017] In some embodiments, the length of each of the one or more additional dosing cycles is about 21 days. In some embodiments, the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some embodiments, each single dose of the bispecific antibody is about equivalent in amount to the Cycle 2, Dose 1 of the bispecific antibody. In some embodiments, each single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0018] In another aspect, the invention features a method of treating a subject having a cell proliferative disorder, comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 and an effective amount of a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises: (a) a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody; and (b) a single dose (Cycle 1 , Dose 1 ) of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 0.9 mg (e.g., about 0.1 mg, about 0.45 mg, or about 0.9 mg). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 1 .8 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the PD-L1 binding antagonist is atezolizumab. In some embodiments, the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg.

[0019] In some embodiments, the length of the first dosing cycle is about 21 days. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the first dosing cycle. In some embodiments, the Cycle 1 , Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of the first dosing cycle. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody and the Cycle 1 , Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in the first dosing cycle.

[0020] In some embodiments, the dosing regimen comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to six (e.g., one, two, three, four, five, or six) additional dosing cycles. In some embodiments, the dosing regimen comprises one to 20 (e.g., one, two, three, four, five, six, seven, eighteen, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) additional dosing cycles.

[0021] In some embodiments, the length of each of the one or more additional dosing cycles is about 21 days. In some embodiments, each of the one or more additional dosing cycles comprises: (a) a single dose of the bispecific antibody; and (b) a single dose of the PD-L1 binding antagonist (e.g., the anti-PD- L1 antibody; e.g., atezolizumab). In some embodiments, each single dose of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 1 of the bispecific antibody. In some embodiments, the single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles. In some embodiments, the single dose of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of each of the one or more additional dosing cycles. In some embodiments, the single dose of the bispecific antibody and the single dose of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in each of the one or more additional dosing cycles. In some embodiments, the PD-L1 binding antagonist is atezolizumab. In some embodiments, each single dose of atezolizumab is about 1200 mg.

[0022] In another aspect, the invention features a method of treating a subject having a cell proliferative disorder, comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 and an effective amount of a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises: (i) a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher than the Cycle 1 , Dose 1 of the bispecific antibody; and (ii) a single dose (Cycle 1 , Dose 1 ) of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab); and (b) the second dosing cycle comprises: (i) a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody; and (ii) a single dose (Cycle 2, Dose 1 ) of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 0.9 mg (e.g., about 0.1 mg, about 0.45 mg, or about 0.9 mg). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 1 .8 mg, about 100 mg, or about 300 mg. In some embodiments, the Cycle 1 , Dose 2 of the bispecific antibody is about 3 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the PD-L1 binding antagonist is atezolizumab. In some embodiments, the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg. In some embodiments, the Cycle 2, Dose 1 of atezolizumab is about 1200 mg.

[0023] In some embodiments, the length of the first dosing cycle is about 21 days. In some embodiments, the Cycle 1 , Dose 1 and the Cycle 1 , Dose 2 of the bispecific antibody are administered to the subject on about Day 1 and about Day 8, respectively, of the first dosing cycle. In some embodiments, the Cycle 1 , Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of the first dosing cycle. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody and the Cycle 1 , Dose 1 of the PD-L1 binding antagonist (e.g., the anti- PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in the first dosing cycle. In some embodiments, the length of the second dosing cycle is about 21 days. In some embodiments, the Cycle 2, Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the second dosing cycle. In some embodiments, the Cycle 2, Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of the second dosing cycle. In some embodiments, the Cycle 2, Dose 1 of the bispecific antibody and the Cycle 2, Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in the second dosing cycle.

[0024] In some embodiments, the dosing regimen comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to six (e.g., one, two, three, four, five, or six) additional dosing cycles. In some embodiments, the dosing regimen comprises one to 20 (e.g., one, two, three, four, five, six, seven, eighteen, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) additional dosing cycles.

[0025] In some embodiments, the length of each of the one or more additional dosing cycles is about 21 days. In some embodiments, each of the one or more additional dosing cycles comprises: (a) a single dose of the bispecific antibody; and (b) a single dose of the PD-L1 binding antagonist (e.g., the anti-PD- L1 antibody; e.g., atezolizumab). In some embodiments, each single dose of the bispecific antibody is about equivalent in amount to the Cycle 2, Dose 1 of the bispecific antibody. In some embodiments, the single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles. In some embodiments, the single dose of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of each of the one or more additional dosing cycles. In some embodiments, the single dose of the bispecific antibody and the single dose of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in each of the one or more additional dosing cycles. In some embodiments, the PD-L1 binding antagonist is atezolizumab. In some embodiments, each single dose of atezolizumab is about 1200 mg.

[0026] In some embodiments, the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered intravenously. In some embodiments the bispecific antibody and the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered on about the same day, the bispecific antibody is administered after (e.g., at least 30 minutes after) the end of the administration of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab). In some embodiments, when the bispecific antibody and the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered on about the same day, the bispecific antibody is administered after (e.g., at least 60 minutes after) the end of the administration of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab).

[0027] In some embodiments of any of the preceding aspects, the bispecific antibody is administered intravenously. In some embodiments of any of the preceding aspects, the method further comprises administering to the subject an effective amount of a corticosteroid. In some embodiments, the corticosteroid is dexamethasone or methylprednisolone. In some embodiments, dexamethasone is administered at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. In some embodiments, dexamethasone is administered at a dose of about 20 mg. In some embodiments, methylprednisolone is administered at a dose of about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg. In some embodiments, methylprednisolone is administered at a dose of about 80 mg. In some embodiments, the corticosteroid is administered prior to (e.g., about one hour prior to) the administration of any dose of the bispecific antibody in the first dosing cycle. In some embodiments, when the bispecific antibody, the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab), and the corticosteroid are administered on about the same day, the corticosteroid is administered after (e.g., at least 60 minutes after) the end of the administration of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) and prior to (e.g., about one hour prior to) the start of the administration of the bispecific antibody. In some embodiments, the subject experiences cytokine release syndrome (CRS), infusion-related reaction (IRR), or immune effector cell-associated neurotoxicity syndrome (ICANS) in a dosing cycle, and the corticosteroid is administered prior to (e.g., about one hour prior to) the administration of the bispecific antibody in the next dosing cycle.

[0028] In some embodiments, the method further comprises administering to the subject an effective amount of tocilizumab. In some embodiments, tocilizumab is administered at a dose of about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, or about 16 mg / kg. In some embodiments, tocilizumab is administered at a dose of about 8 mg / kg. In some embodiments, each dose of tocilizumab is about 12 mg / kg. In some embodiments, the subject experiences CRS after being administered the bispecific antibody, and wherein dexamethasone is administered to the subject about every 6 hours. In some embodiments, the subject experiences CRS after being administered the bispecific antibody, and tocilizumab and dexamethasone are administered to the subject about every 6 hours. In some embodiments, dexamethasone is administered at a dose of about 10 mg; and / or wherein tocilizumab is administered at a dose of about 8 mg / kg or about 12 mg / kg. In some embodiments, tocilizumab is administered intravenously. In some embodiments, the corticosteroid is administered intravenously.

[0029] In some embodiments of any of the preceding aspects, the method further comprises administering to the subject an effective amount of an antihistamine. In some embodiments, the antihistamine is diphenhydramine. In some embodiments, diphenhydramine is administered at a dose of from about 25 mg to about 50 mg (e.g., from about 25 mg to about 45 mg, from about 25 mg to about 40 mg, from about 25 mg to about 35 mg, from about 25 mg to about 30 mg, from about 30 mg to about 50 mg, from about 35 mg to about 50 mg, from about 40 mg to about 50 mg, from about 45 mg to about 50 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, the antihistamine is administered prior to (e.g., at least about 30 minutes prior to) the administration of any dose of the bispecific antibody. In some embodiments, the antihistamine is administered orally.

[0030] In some embodiments of any of the preceding aspects, the method further comprises administering to the subject an effective amount of acetaminophen or paracetamol. In some embodiments, acetaminophen or paracetamol is administered at a dose of from about 500 mg to about 1 ,000 mg (e.g., from about 500 mg to about 900 mg, from about 500 mg to about 800 mg, from about 500 mg to about 700 mg, from about 500 mg to about 600 mg, from about 600 mg to about 1 ,000 mg, from about 700 mg to about 1 ,000 mg, from about 800 mg to about 1 ,000 mg, from about 900 mg to about 1 ,000 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1 ,000 mg). In some embodiments, acetaminophen or paracetamol is administered prior to (e.g., at least about 30 minutes prior to) the administration of any dose of the bispecific antibody. In some embodiments, acetaminophen or paracetamol is administered orally.

[0031] In some embodiments of any of the preceding aspects, the bispecific antibody comprises: (a) a first antigen-binding domain that binds CCR8, wherein the first antigen-binding domain comprises the following six complementarity-determining regions (CDRs): (i) a heavy chain CDR 1 (CDR-H1 ) comprising the amino acid sequence TYAMG (SEQ ID NO: 1 ); (ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO: 2); (iii) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3); (iv) a light chain CDR 1 (CDR-L1 ) comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4); (v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and (vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6); (b) a second antigen-binding domain that binds CD3, wherein the second antigen-binding domain comprises the following six CDRs: (i) a CDR-H1 comprising the amino acid sequence NYYIH (SEQ ID NO: 7); (ii) a CDR-H2 comprising the amino acid sequence WIYPGDGNTKYNEKFKG (SEQ ID NO: 8); (iii) a CDR-H3 comprising the amino acid sequence DSYSNYYFDY (SEQ ID NO: 9); (iv) a CDR-L1 comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 10); (v) a CDR-L2 comprising the amino acid sequence WASTRES (SEQ ID NO: 11 ); and (vi) a CDR-L3 comprising the amino acid sequence TQSFILRT (SEQ ID NO: 12); and (c) a third antigen-binding domain that binds CCR8, wherein the third antigen-binding domain comprises the following six CDRs: (i) a CDR-H1 comprising the amino acid sequence TYAMG (SEQ ID NO: 1 ); (ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO: 2); (iii) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3); (iv) a CDR-L1 comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4); (v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and (vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6).

[0032] In some embodiments, the first antigen-binding domain comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, and wherein: (a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); and / or (b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat). In some embodiments, the second antigen-binding domain comprises a VL domain and a VH domain, and wherein the VL domain comprises a glutamic acid residue at position 38 and the VH domain comprises a lysine residue at position 39 (numbering according to Kabat). In some embodiments, the third antigen-binding domain comprises a VL domain and a VH domain, and wherein: (a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); and / or (b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat).

[0033] In some embodiments, the first antigen-binding domain comprises: (i) a VH domain comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 13; (ii) a VL domain comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 14; or (Hi) a VH domain as in (i) and a VL domain as in (ii). In some embodiments, the first antigen-binding domain comprises: (i) a VH domain comprising the amino acid sequence of SEQ ID NO: 13; (ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 14; or (Hi) a VH domain as in (i) and a VL domain as in (ii). In some embodiments, the second antigen-binding domain comprises: (i) a VH domain comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 15; (ii) a VL domain comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 16; or (Hi) a VH domain as in (i) and a VL domain as in (ii). In some embodiments, the second antigen-binding domain comprises: (i) a VH domain comprising the amino acid sequence of SEQ ID NO: 15; (ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 16; or (Hi) a VH domain as in (i) and a VL domain as in (ii). In some embodiments, the third antigen-binding domain comprises: (i) a VH domain comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 13; (ii) a VL domain comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 14; or (Hi) a VH domain as in (i) and a VL domain as in (ii). In some embodiments, the third antigen-binding domain comprises: (i) a VH domain comprising the amino acid sequence of SEQ ID NO: 13; (ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 14; or (Hi) a VH domain as in (i) and a VL domain as in (ii).

[0034] In some embodiments, each of the first, the second, and / or the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain. In some embodiments, each of the first, the second, and the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, and wherein: (a) the Fab light chain of the first antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the first antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat); (b) the Fab light chain of the second antigen-binding domain comprises a lysine residue at position 133, and the Fab heavy chain of the second antigen-binding domain comprises a glutamic acid residue at position 183 (numbering according to Kabat); and / or (c) the Fab light chain of the third antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the third antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat). In some embodiments, the second antigen-binding domain and the third antigen-binding domain are fused to each other. In some embodiments, the second antigen-binding domain and the third antigenbinding domain are fused to each other via a peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of SEQ ID NO: 21 . In some embodiments, each of the second antigen-binding domain and the third antigen-binding domain is a Fab molecule, and wherein the third antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen-binding domain.

[0035] In some embodiments, the bispecific antibody further comprises an Fc domain comprising a first subunit and a second subunit. In some embodiments, the Fc domain is an IgG Fc domain. In some embodiments, the Fc domain is an IgG 1 Fc domain. In some embodiments, the Fc domain is a human IgG Fc domain. In some embodiments, the Fc domain comprises a modification promoting the association of the first subunit and the second subunit of the Fc domain. In some embodiments, each of the first and the second subunit comprises an alanine residue at position 234, an alanine residue at position 235, and a glycine residue at position 329 (numbering according to Kabat EU index).

[0036] In some embodiments, the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 1) domain, a first CH2 (CH2i) domain, a first CH3 (CH3i) domain, a second CH1 (CHI 2) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain. In some embodiments, the first subunit comprises one or more heavy chain constant domains selected from a first CH2 (CH2i) domain and / or a first CH3 (CH3i) domain; and the second subunit comprises one or more heavy chain constant domains selected from a second CH2 (CH22) domain and / or a second CH3 (CH32) domain. In some embodiments, the first subunit comprises one or more heavy chain constant domains selected from a first CH2 (CH2i) domain and / or a first CH3 (CH3i) domain; and the second subunit comprises one or more heavy chain constant domains selected from a second CH2 (CH22) domain and / or a second CH3 (CH32) domain.

[0037] In some embodiments, each of the CH3i and CH32 domains comprises a protuberance or cavity, and wherein the protuberance or cavity in the CH3i domain is positionable in the cavity or protuberance, respectively, in the CH32 domain. In some embodiments, the CH3i and CH32 domains meet at an interface between said protuberance and cavity. In some embodiments, the CH2i and CH22 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2i domain is positionable in the cavity or protuberance, respectively, in the CH22 domain. In some embodiments, the CH2i and CH22 domains meet at an interface between said protuberance and cavity. In some embodiments, the first subunit comprises a tryptophan residue at position 366 (numbered according to Kabat EU index), and the second subunit comprises a serine residue at position 366, an alanine residue at position 368, and a valine residue at position 407 (numbered according to Kabat EU index).

[0038] In some embodiments, each of the first antigen-binding domain and the second antigen-binding domain is a Fab molecule, wherein the bispecific antibody comprises an Fc domain comprising a first subunit and a second subunit, and wherein: (a) the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit; and (b) the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit. In some embodiments, each of the first, the second, and the third antigen-binding domain is a Fab molecule, wherein the bispecific antibody comprises an Fc domain comprising a first subunit and a second subunit, and wherein: (a) the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit; (b) the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit; and (c) the third antigenbinding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen-binding domain.

[0039] In some embodiments, the bispecific antibody comprises: (a) a polypeptide comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 17; (b) a first and a second polypeptide each comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 18; (c) a polypeptide comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 19; and (d) a polypeptide comprising an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical) sequence identity to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the bispecific antibody comprises: (a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 17; (b) a first and a second polypeptide each comprising the amino acid sequence of SEQ ID NO: 18; (c) a polypeptide comprising the amino acid sequence of SEQ ID NO: 19; and (d) a polypeptide comprising the amino acid sequence of SEQ ID NO: 20.

[0040] In some embodiments of any of the preceding aspects, the subject is a human.

[0041] In some embodiments of any of the preceding aspects, the subject (a) has progressed after at least one available standard therapy; and / or (b) is one for whom all available standard therapy has been proven to be ineffective or intolerable or is contraindicated.

[0042] In some embodiments of any of the preceding aspects, the subject’s age is 18 years or older.

[0043] In some embodiments of any of the preceding aspects, the cell proliferative disorder is a cancer. In some embodiments, the cell proliferative disorder is a solid tumor malignancy. In some embodiments, the cell proliferative disorder is a locally advanced, recurrent, or metastatic incurable solid tumor malignancy. In some embodiments, the cell proliferative disorder is non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), cutaneous melanoma, triple-negative breast cancer (TNBC), urothelial carcinoma (UCC), esophageal cancer, gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, clear cell renal cell carcinoma (ccRCC), or hepatocellular carcinoma (HOC).

[0044] In some embodiments of any of the preceding aspects, the subject is checkpoint inhibitor (CPI)- naTve. In some embodiments, the cell proliferation disorder is NSCLC, and wherein the subject has a tumor cell (TC) PD-L1 expression of > 50%, or an immune cell (IC) PD-L1 expression of > 10%. In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a combined TC / IC PD-L1 expression of > 20. In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a combined TC / IC PD-L1 expression of > 1 and < 19. In some embodiments, the combined TC / IC PD-L1 expression is determined as tumor area positivity (TAP) or combined positive score (CPS). In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 20%. In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 5% to > 19%. In some embodiments, TAP score is based on visual estimation of the area covered by PD-L1 positive TC / IC relative to the total tumor area. In some embodiments, TPS score is the number of PD-L1 positive TC divided by the total viable tumor cells multiplied by 100. In some embodiments, CPS score is the number of PD-L1 positive TC / IC, divided by the total number of viable tumor cells multiplied by 100.

[0045] In some embodiments of any of the preceding aspects, the subject is CPI-experienced. In some embodiments, the cell proliferation disorder is NSCLC, HNSCC, gastric cancer, GEJ adenocarcinoma, HCC, ccRCC, TNBC, or UCC, and wherein the subject has a TC, IC, or combined TC / IC PD-L1 expression of > 1 or 1%. In some embodiments, the cell proliferation disorder is esophageal cancer, and wherein the subject has a TC, IC, or combined TC / IC PD-L1 expression of > 10 or 10%. In some embodiments, the combined TC / IC PD-L1 expression is determined as CPS, TAP, or tumor proportion score (TPS). In some embodiments, the cell proliferation disorder is NSCLC, and wherein the subject has an IC PD-L1 expression of > 1%. In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 5%. In some embodiments, the cell proliferation disorder is gastric cancer or GEJ adenocarcinoma, and wherein the subject has a PD-L1 TAP of > 1%. In some embodiments, the cell proliferation disorder is ccRCC, TNBC, or UCC, and wherein the subject has an IC PD-L1 expression of > 1%. In some embodiments, the cell proliferation disorder is esophageal cancer, and wherein the subject has a PD-L1 TAP of > 10%.

[0046] In some embodiments, the subject’s tumor comprises a targetable somatic alteration, and the subject has experienced disease progression during or after treatment, or intolerance to treatment, with a targeted agent. In some embodiments, the targetable somatic alteration comprises a somatic alteration involving epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS protooncogene 1 (ROS1 ), proto-oncogene B-Raf (BRAF) V600E, neurotrophic tyrosine receptor kinase (NTRK), MET proto-oncogene (MET), RET proto-oncogene (RET), or Kirsten rat sarcoma virus (KRAS). In some embodiments, the cell proliferation disorder is cutaneous melanoma, wherein the subject’s tumor comprises a BRAFV600 mutation, and wherein the subject has experienced disease progression during or after treatment, or intolerance to treatment, with one or more serine / threonine-protein kinase B-Raf (BRAF) inhibitors and / or one or more mitogen-activated protein kinase kinase (MEK) inhibitors.

[0047] In some embodiments of any of the preceding aspects, the cell proliferative disorder is NSCLC. In some embodiments, the cell proliferative disorder is HNSCC. In some embodiments, the HNSCC is HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx.

[0048] In some embodiments of any of the preceding aspects, the method further comprises determining the expression level of programmed death-ligand 1 (PD-L1 ) in a sample obtained from the subject. In some embodiments, the sample is a tumor sample. In some embodiments, the sample is a fresh tumor sample, a formalin-fixed, paraffin-embedded tumor sample, or an archival tumor sample. In some embodiments, the sample comprises tumor cells, tumor infiltrating immune cells, stromal cells, and any combinations thereof. In some embodiments, the sample is obtained prior to the first dosing cycle. In some embodiments, PD-L1 is absent from the sample when it comprises 0% of the sample. In some embodiments, PD-L1 is present in the sample when it comprises more than 0% of the sample. In some embodiments, PD-L1 is expressed in tumor cells covering at least 1 % (e.g., at least 1 %, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%) of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor cells covering at least 5% of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor cells covering at least 10% of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor cells covering at least 20% of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor cells covering at least 50% of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor-infiltrating immune cells covering at least 1 % (e.g., at least 1 %, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 1 1 %, at least 12%, at least 13%, at least 14%, or at least 15%) of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor-infiltrating immune cells covering at least 5% of the tumor sample area. In some embodiments, PD-L1 is expressed in tumorinfiltrating immune cells covering at least 10% of the tumor sample area.

[0049] BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG. 1 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on CCR8+ Treg depletion and CCR8+ Treg cell count of T cells isolated from peripheral blood mononuclear cells (PBMCs) of four healthy donors.

[0051] FIG. 2 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on the depletion of CD8+, conventional CD4+, and Treg cells in T cells isolated from PBMCs of four healthy donors. Conv. = conventional.

[0052] FIG. 3 is a line graph showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on the killing of CCR8-expressing TALL-1 target cells by PBMCs isolated from eight healthy donors.

[0053] FIG. 4 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on the depletion of CCR8+Treg cells in dissociated human lung tumor samples.

[0054] FIG. 5 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on the cell counts of CD8+, conventional CD4+, and Treg cells in cultured, dissociated human lung tumor samples. Conv. = conventional.

[0055] FIG. 6 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on CD8+and CD4+T cell activation in human PBMC:TALL-1 co-cultures. The human PBMCs were from eight healthy donors. T = T cells.

[0056] FIG. 7 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on interleukin (IL)-2, IL-6, interferon (IFN)-y, and tumor necrosis factor (TNF) release from human PBMC:TALL-1 co-cultures. The human PBMCs were from eight healthy donors.

[0057] FIG. 8 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on CD8+and CD4+T cell activation in human PBMCs. T = T cells. The human PBMCs were from eight healthy donors. FIG. 9 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on IL-2, IL-6, IFN-y, and TNF release from human PBMCs. The human PBMCs were from eight healthy donors.

[0058] FIG. 10 is a series of line graphs showing the effect of a single dose of the anti-CCR8 / anti-CD3 bispecific antibody on the growth of E0771 syngeneic mammary tumors in hu.CD3E.tg.B6N mice. The vehicle of the bispecific antibody was histidine buffer (20 mM histidine acetate, 240 mM sucrose, 0.02% polysorbate 20; pH 5.5). The raw data for each mouse and the group fit are depicted. Thin lines indicate data from individual animals. Thick lines indicate group fits. In treatment groups (Groups 2-4), dashed lines indicate the fitted data for control group (Group 1 ) and provide a reference of the activity from the control group.

[0059] FIG. 11 is a series of bar graphs showing the effect of a single dose of the anti-CCR8 / anti-CD3 bispecific antibody on the depletion of intratumoral CCR8+Treg cells and total Treg cells in E0771 syngeneic mammary tumors in hu.CD3E.tg.B6N mice. The abundance of Treg cells was determined by flow cytometry three days (D3) or seven days (D7) after the treatment with the anti-CCR8 / anti-CD3 bispecific antibody. The vehicle of the bispecific antibody was histidine buffer (20 mM histidine acetate, 240 mM sucrose, 0.02% polysorbate 20; pH 5.5). The graphs show the medians and ranges of the data. * = p<0.05; ** = p<0.01 ; *“ = p<0.001 ; *“* = p<0.0001 .

[0060] FIG. 12 is a series of bar graphs showing the effect of a single dose of the anti-CCR8 / anti-CD3 bispecific antibody on the proliferation of intratumoral CD8+T cells and conventional CD4+T cells in E0771 syngeneic mammary tumors in hu.CD3E.tg.B6N mice. The abundance of CD8+T cells and conventional CD4+T cells was determined by flow cytometry three days (D3) or seven days (D7) after the treatment with the anti-CCR8 / anti-CD3 bispecific antibody. The vehicle of the bispecific antibody was histidine buffer (20 mM histidine acetate, 240 mM sucrose, 0.02% polysorbate 20; pH 5.5). The graphs show the medians and ranges of the data. * = p<0.05.

[0061] FIG. 13 is a series of bar graphs showing the effect of a single dose of the anti-CCR8 / anti-CD3 bispecific antibody on the proportion of proliferative (Ki-67+) and granzyme B (GzmB)-producing CD8+T cells in E0771 syngeneic mammary tumors in hu.CD3E.tg.B6N mice. The abundance of Ki-67+and GzmB+CD8+T cells was determined by flow cytometry three days (D3) or seven days (D7) after the treatment with the anti-CCR8 / anti-CD3 bispecific antibody. The vehicle of the bispecific antibody was histidine buffer (20 mM histidine acetate, 240 mM sucrose, 0.02% polysorbate 20; pH 5.5). The graphs show the medians and ranges of the data.

[0062] FIG.14 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on the growth of EMT6 syngeneic tumors in BALB-c mice. An anti-glycoprotein 120 (gp120) antibody was used as a control. The raw data for each mouse and group fit are depicted. Thin lines indicate data from individual animals. Thick lines indicate group fits. In Groups 2-8, dashed lines indicate the fitted data for control group (Group 1 ) and provide a reference of the activity from the control group.

[0063] FIG. 15 is a line graph showing serum concentrations (mean ± standard deviation (SD)) of the anti-CCR8 / anti-CD3 bispecific antibody following single-dose intravenous (IV) administrations to hu.CD3E.tg.B6N mice bearing E0771 syngeneic mammary tumors. The anti-CCR8 / anti-CD3 bispecific antibody was administered on Day 0, and time refers to days postdose. The dashed line denotes the minimum quantifiable concentration (MQC) (0.01172 pg / mL). For groups dosed with 0.013 mg / kg (Group 2) or 0.04 mg / kg (Group 3) anti-mCCR8 / hCD3 bispecific antibody, the serum concentrations of the drug were below the MQC at some timepoints; therefore, those points are not shown. Grp = Group.

[0064] FIG. 16 is a line graph showing serum concentrations of the anti-CCR8 / anti-CD3 bispecific antibody in individual cynomolgus monkeys following IV administration. The lower limit of quantification is 0.1 pg / mL.

[0065] FIG. 17 is a line graph showing mean (± SD) sex-combined serum concentration-time profiles of the anti-CCR8 / anti-CD3 bispecific antibody following repeat-dose IV and subcutaneous (SC) administration to cynomolgus monkeys.

[0066] FIG. 18 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on percent change from baseline of absolute numbers of FOXP3+ CD25+ Treg-Cells (referred to as Treg- 2) in male (left) and female (right) cynomolgus monkeys. FOXP3 = forkhead box P3; IV = intravenous; SC = subcutaneous; Anti-CCR8 / CD3 TDB = anti-CCR8 / anti-CD3 bispecific antibody.

[0067] FIG. 19 is a schematic showing the study design of the Phase la portion of the study described in Example 2, which uses the anti-CCR8 / anti-CD3 bispecific antibody as a single agent. Actual patient counts vary. Up to approximately 10 additional patients are enrolled in backfill cohorts. BOIN = Bayesian optimal interval; ccRCC = clear cell renal cell carcinoma; CPI = checkpoint inhibitor; DL = dose level; DLT = dose-limiting toxicity; HCC = hepatocellular carcinoma; HNSCC = head and neck squamous cell carcinoma; MAD = maximum administered dose; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; PD = pharmacodynamic; PK = pharmacokinetic; Q3W = every 3 weeks; TBD = to be determined; TNBC = triple-negative breast cancer; UCC = urothelial carcinoma; CCR8 TDB = anti- CCR8 / anti-CD3 bispecific antibody.

[0068] FIG. 20 is a schematic showing the study design of the Phase lb portion of the study described in Example 2, which uses the anti-CCR8 / anti-CD3 bispecific antibody in combination with atezolizumab. Actual patient counts vary. Up to approximately 10 additional patients are enrolled in backfill cohorts. BOIN = Bayesian optimal interval; CPI = checkpoint inhibitor; DL = dose level; DLT = dose-limiting toxicity; HNSCC = head and neck squamous cell carcinoma; MAD = maximum administered dose; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; PD = pharmacodynamic; PK = pharmacokinetic; Q3W = every 3 weeks; TBD = to be determined; CCR8 TDB = anti-CCR8 / anti-CD3 bispecific antibody.

[0069] FIG. 21 is a schematic showing the study design of the Phase la one-step dose fractionation schedule. * Hospitalization starts from end of the infusion of the anti-CCR8 / anti-CD3 bispecific antibody and is implemented for Cycles > 2 based on tolerability of prior infusions of the anti-CCR8 / anti-CD3 bispecific antibody. D = day; DLT = dose-limiting toxicity; CCR8 TDB = anti-CCR8 / anti-CD3 bispecific antibody.

[0070] FIG. 22 is a schematic showing the study design of the Phase lb one-step dose fractionation schedule. * Hospitalization starts from end of the infusion of the anti-CCR8 / anti-CD3 bispecific antibody and is implemented for Cycles > 2 based on tolerability of prior infusions of the anti-CCR8 / anti-CD3 bispecific antibody. D = day; DLT = dose-limiting toxicity; CCR8 TDB = anti-CCR8 / anti-CD3 bispecific antibody. FIGS. 23A and 23B are schematics showing the study design for crossing over from Phase la to Phase lb for Phase la patients. FIG. 23A shows the timing of potential crossover from Phase la to Phase lb due to progressive disease (PD). FIG. 23B shows an exemplary scheme of the potential crossover from Phase la to Phase lb. DLT = dose-limiting toxicity; PD = progressive disease; CCR8 TDB = anti- CCR8 / anti-CD3 bispecific antibody.

[0071] FIG. 24 is a line graph showing the toxicokinetic profile of the anti-CCR8 / anti-CD3 bispecific antibody administered to cynomolgus monkeys intravenously or subcutaneously. IV = intravenous; SC = subcutaneous; BLOQ = below the limit of quantification.

[0072] FIG. 25 is a schematic showing the structure of the minimal physiologically-based pharmacokinetic (mPBPK) model for the prediction of pharmacokinetics (PK), receptor occupancy (RO), and Treg depletion of the anti-CCR8 / anti-CD3 bispecific antibody across species. CL = clearance; TDB = anti-CCR8 / anti-CD3 bispecific antibody; PD = pharmacodynamics.

[0073] FIG. 26 is a series of line graphs showing the toxicological profile of the anti-CCR8 / anti-CD3 bispecific antibody assessed in cynomolgus monkeys following Good Laboratory Practice (GLP). The anti-CCR8 / anti-CD3 bispecific antibody was given to cynomolgus monkeys once a week for 42 days at a dosage of 3 mg / kg or 15 mg / kg for intravenous delivery and 15 mg / kg for subcutaneous delivery. GLP = Good Laboratory Practice; Tox = toxicology; SC = subcutaneous; Cone. = concentration.

[0074] FIG. 27 is a series of line graphs showing the results of a pilot toxicological study of the anti- CCR8 / anti-CD3 bispecific antibody in cynomolgus monkeys. The anti-CCR8 / anti-CD3 bispecific antibody was given to cynomolgus monkeys once a week for 21 days at a dosage of 1 , 3, or 10 mg / kg for intravenous delivery. Q1 W = once a week; Cone. = concentration; cyno = cynomolgus; PD = pharmacodynamics.

[0075] FIG. 28 is a series of line graphs showing the pharmacokinetics (PK) and receptor occupancy (RO) of the anti-CCR8 / anti-CD3 bispecific antibody in the blood (upper panels) or tumor (lower panels) of human subjects predicted using the mPBPK model. The predicted PK, CCR8 RO, CD3 RO, and bispecific antibody-CCR8 receptor-CD3 trimer formation are shown for the bispecific antibody given once every three weeks at a dosage of 0.1 , 10, or 1000 mg. Q3W = once every three weeks; PK = pharmacokinetics; RO = receptor occupancy; Treg = regulatory T cells.

[0076] FIG. 29 is a series of line graphs showing the PK and RO of the anti-CCR8 / anti-CD3 bispecific antibody in the blood (upper panels) or tumor (lower panels) of human subjects predicted using the mPBPK model based on the projected dose range of the anti-CCR8 / anti-CD3 bispecific antibody. The predicted PK, CCR8 RO, and CD3 RO are shown for the bispecific antibody given once every three weeks at a dosage of 0.1 , 0.3, or 0.6 mg. Q3W = once every three weeks; PK = pharmacokinetics; RO = receptor occupancy; Treg = regulatory T cells.

[0077] FIG. 30A is a line graph showing the receptor occupancy of the anti-CCR8 / anti-CD3 bispecific antibody in tumor of human subjects predicted using the mPBPK model. The receptor occupancy on Day 21 following the treatment with the bispecific antibody at various dosages is shown. Shaded area indicates the does range where CCR8 has 90% receptor occupancy. RO = receptor occupancy.

[0078] FIG. 30B is an area graph showing the percentage of free and antibody-occupied CCR8 in human subjects predicted using the mPBPK model. The antibody-occupied population of CCR8 is further divided into bispecific antibody-CCR8 receptor dimer- and bispecific antibody-CCR8 receptor-CD3 trimer- forming subpopulations.

[0079] FIG. 30C is a line graph showing the average number of bispecific antibody-CCR8 receptor-CD3 trimer formed by the anti-CCR8 / anti-CD3 bispecific antibody on CCR8+ Treg cells in human subjects predicted using the mPBPK model. The average number of bispecific antibody-CCR8 receptor-CD3 trimer formed on Day 21 following the treatment with the bispecific antibody at various dosages is shown. Avg = average; Treg cell = regulatory T cell.

[0080] FIG. 30D is a line graph showing the same predicted bispecific antibody-CCR8 receptor-CD3 trimer formation as in FIG. 30C, except that the amount of trimer formation is represented by the percentage of the maximum number of trimers formed per cell.

[0081] FIG. 31 is a series of line graphs showing the results of a sensitivity analysis assessing the impact of different pharmacological parameters on the prediction outputs of the mPBPK model. The impact of the CCR8 or CD3 affinity of the anti-CCR8 / anti-CD3 bispecific antibody, the rate of nonspecific clearance, the CCR8+ Treg cell count in tumor, the CD8+ T cell count in tumor, and tumor partitioning on the predicted average bispecific antibody-CCR8 receptor-CD3 trimer count per CCR8+ Treg cell in human subjects on Day 21 following the treatment with the anti-CCR8 / anti-CD3 bispecific antibody was assessed at different dosages of the bispecific antibody. CLns = nonspecific clearance; Treg cell = regulatory T cell.

[0082] FIG. 32 is a series of line graphs showing the results of a sensitivity analysis assessing the impact of different pharmacological parameters on the prediction outputs of the mPBPK model. The impact of the CCR8 or CD3 affinity of the anti-CCR8 / anti-CD3 bispecific antibody, the rate of nonspecific clearance, the CCR8+ Treg cell count in tumor, the CD8+ T cell count in tumor, and tumor partitioning on the predicted CCR8 and CD3 RO in human subjects on Day 21 following the treatment with the anti- CCR8 / anti-CD3 bispecific antibody was assessed at different dosages of the bispecific antibody. Frac = fraction; CLns = nonspecific clearance; Treg cell = regulatory T cell.

[0083] FIG. 33A is a line graph showing the average concentration of the anti-CCR8 / anti-CD3 bispecific antibody in TALL cells in an in vitro cytotoxicity assay predicted using the mPBPK model. The model predicted the half-maximal effective concentration (ECso) of the bispecific antibody. Cavg = average concentration; d21 = Day 21 ; ECso = half-maximal effective concentration

[0084] FIG. 33B is a line graph showing the tumor concentration and average tumor concentration of the anti-CCR8 / anti-CD3 bispecific antibody in human subjects over time predicted using the mPBPK model. The predicted concentration over time is shown for tumors treated once every three weeks with various dosages of the bispecific antibody. PK = pharmacokinetics; Q3W = once every three weeks; Cone = concentration; Avg = average.

[0085] FIG. 34 is a series of bar graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on the CCR8+ Treg cell count and CD8+ T cell count in E0771 tumors in human CD3 transgenic mice. Treg = regulatory T cell; CCR8 TDB = anti-CCR8 / anti-CD3 bispecific antibody.

[0086] FIG. 35 is a line graph showing the serum concentration of the anti-CCR8 / anti-CD3 bispecific antibody over time in mice treated with 0.013, 0.04, or 1 mg / kg of the bispecific antibody. Cone. = concentration. FIG. 36A is a series of line graphs showing the CCR8+ Treg cell depletion, CD8+ T cell expansion, and tumor cell killing mediated by the anti-CCR8 / anti-CD3 bispecific antibody in human subjects over time predicted using the mPBPK model. Treg cells = regulatory T cells.

[0087] FIG. 36B is a series of line graphs showing the same predicted CCR8+ Treg cell depletion, CD8+ T cell expansion, and tumor cell killing mediated by the anti-CCR8 / anti-CD3 bispecific antibody in human subjects over time as in FIG. 36A, except that the number of cells is represented by the percentage of baseline.

[0088] FIG. 37 is a series of line graphs showing the CCR8 receptor occupancy, CD8+ T to regulatory T cell ratio, and bispecific antibody-CCR8 receptor-CD3 trimer formation in human subjects following the treatment with the anti-CCR8 / anti-CD3 bispecific antibody predicted using the mPBPK model. RO = receptor occupancy; Treg = regulatory T cell; Avg = average.

[0089] FIG. 38 is a series of line graphs showing the effect of the anti-CCR8 / anti-CD3 bispecific antibody on CCR8+ Treg cell count, CD8+ T cell count, and tumor size in human subjects over time predicted using the mPBPK model. Treg = regulatory T cell.

[0090] DETAILED DESCRIPTION OF THE INVENTION

[0091] I. General Techniques

[0092] The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001 ) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F .M. Ausubel, et al., eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.l. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.l. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991 ); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. De Vita et al., eds., J.B. Lippincott Company, 1993).

[0093] II. Definitions It is to be understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments. As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.

[0094] As used herein, the term “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In some instances, “about” a value refers to the value ± 10%.

[0095] As used herein interchangeably, the “amount,” “level,” or “expression level” of a biomarker is a detectable level in a biological sample. “Expression” generally refers to the process by which information (e.g., gene-encoded and / or epigenetic) is converted into the structures present and operating in the cell. Therefore, as used herein, “expression” may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and / or polypeptide modifications (e.g., posttranslational modification of a polypeptide). Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and / or polypeptide modifications (e.g., posttranslational modification of a polypeptide) shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a post-translational processing of the polypeptide, e.g., by proteolysis. “Expressed genes” include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs). Expression levels can be measured by methods known to one skilled in the art and also disclosed herein. The presence and / or expression level / amount of various biomarkers described herein in a sample can be analyzed by a number of methodologies, many of which are known in the art and understood by the skilled artisan, including, but not limited to, immunohistochemistry (IHC), Western blot analysis, immunoprecipitation, molecular binding assays, enzyme-linked immunosorbent assay (ELISA), enzyme-linked immuno-filtration assay (ELIFA), fluorescence activated cell sorting (FACS), MASSARRAY®, proteomics, quantitative blood based assays (e.g., Serum ELISA), biochemical enzymatic activity assays, in situ hybridization, fluorescence in situ hybridization (FISH), Southern analysis, Northern analysis, whole genome sequencing, massively parallel DNA sequencing (e.g., next-generation sequencing), NANOSTRING®, polymerase chain reaction (PCR) including quantitative real time PCR (qRT-PCR) and other amplification type detection methods, such as, for example, branched DNA, SISBA, TMA and the like, RNA-seq, microarray analysis, gene expression profiling, and / or serial analysis of gene expression (SAGE), as well as any one of the wide variety of assays that can be performed by protein, gene, and / or tissue array analysis. Multiplexed immunoassays such as those available from Rules Based Medicine or Meso Scale Discovery (MSD) may also be used.

[0096] As used herein, the terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers. The terms “early-stage cancer” or “early-stage tumor,” as used herein, refers to a cancer that is not invasive or metastatic or is classified as a Stage 0, I, or II cancer. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include bladder cancer, squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer (SCLC), NSCLC, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, hepatoma, breast cancer (including metastatic breast cancer), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, tumors of the biliary tract, as well as head and neck cancer and multiple myeloma.

[0097] As used herein, the term “tumor” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer”, “cancerous”, “cell proliferative disorder”, “proliferative disorder,” and “tumor” are not mutually exclusive as referred to herein.

[0098] As used herein, the term “disorder” refers to any condition that would benefit from treatment including, but not limited to, chronic and acute disorders or diseases including those pathological conditions which predispose the mammal to the disorder in question.

[0099] As used herein, the terms “cell proliferative disorder” and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. In another embodiment, the cell proliferative disorder is a tumor.

[0100] As used herein, the term “treatment” (and grammatical variations thereof, such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual being treated and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, the invention can delay development of a disease or to slow the progression of a disease.

[0101] As used herein, the term “administering” (and grammatical variations thereof, such as “administer” or “administration”) refers to a method of giving a dosage of a compound (e.g., an anti- CCR8 / anti-CD3 bispecific antibody and / or a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab)) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including an anti-CCR8 / anti-CD3 bispecific antibody and / or a PD-L1 binding antagonist (e.g., an anti-PD- L1 antibody; e.g., atezolizumab)) to a subject. The compounds and / or compositions utilized in the methods described herein can be administered, for example, intravenously (e.g., by intravenous infusion), subcutaneously, intramuscularly, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in creams, or in lipid compositions. The method of administration can vary depending on various factors (e.g., the compound or composition being administered, and the severity of the condition, disease, or disorder being treated).

[0102] As used herein, a “subject,” “patient,” or “individual” refers to a mammal. Mammals include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), domesticated animals (e.g., cows, sheep, cats, dogs, and horses), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject, patient, or individual is a human.

[0103] As used herein, the term “reduce” or “inhibit” refers to the ability to cause an overall decrease, for example, of about 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater. In certain embodiments, reduce or inhibit can refer to the reduction or inhibition of undesirable events, such as cytokine-driven toxicities (e.g., CRS, IRR, and / or ICANS, following treatment with an anti-CCR8 / anti-CD3 bispecific antibody using the fractionated, dose-escalation dosing regimen of the invention relative to treatment with an anti-CCR8 / anti-CD3 bispecific antibody using a non-fractioned dosing regimen. In other embodiments, reduce or inhibit can refer to effector function of an antibody that is mediated by the antibody Fc region, such effector functions specifically including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).

[0104] As used herein, the term “protein” refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed protein as well as any form of the protein that results from processing in the cell. The term also encompasses naturally occurring variants of the protein, e.g., splice variants or allelic variants.

[0105] As used herein, the term “Kabat numbering system” refers to a numbering system by Kabat et al. {Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991 )) that numbers a residue in the variable domain (approximately residues 1 -107 of the light chain and residues 1 -1 13 of the heavy chain) of an immunoglobulin. The “EU numbering system” or “EU index” refers to an alternative numbering system by Kabat et al. (e.g., the EU index reported in Kabat et al., supra) that numbers residue in an immunoglobulin heavy chain constant region. The “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody.

[0106] As used herein, the term “antibody” is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies (mAbs), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.

[0107] As used herein, the term “T cell-dependent bispecific antibody” or “TDB” refers to a bispecific antibody that binds a first antigen (e.g., CCR8) and a second antigen that is an activating T cell antigen (e.g., CD3).

[0108] As used herein, the term “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0109] As used herein interchangeably, the terms “full-length antibody,” “intact antibody,” and “whole antibody” refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

[0110] As used herein, the term “binding domain” refers to a part of a compound or a molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains include, but are not limited to antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab’2, scFv antibodies, small modular immunopharmaceutical (SMIP), domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and / or VL domains of antibodies), receptors, ligands, aptamers, and other molecules having an identified binding partner.

[0111] As used herein, the term “Fc region” or “Fc domain” refers to a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0112] As used herein, the “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgGa, IgGs, lgG4, IgAi, and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, e, y, and p, respectively.

[0113] As used herein, the term IgG “isotype” or “subclass” refers to any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.

[0114] As used herein, the term “Framework” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1 -H1 (L1 )-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0115] As used herein, a “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91 -3242, Bethesda MD (1991 ), vols. 1 -3. In one embodiment, for the VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for the VH, the subgroup is subgroup III as in Kabat et al., supra.

[0116] As used herein, the term “acceptor human framework” refers to a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0117] As used herein, the term “humanized antibody” refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody may comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0118] As used herein, the term “human antibody” refers to an antibody which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991 ); Marks et al., J. Mol. Biol. 222:581 (1991 )). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol. 147(1 ):86-95 (1991 ). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001 ). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized XENOMOUSE® (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE® technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology.

[0119] As used herein, the term “chimeric” antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0120] As used herein, the term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology, 6thed., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991 ).

[0121] As used herein, the term “hypervariable region” or “HVR” refers to each of the regions of an antibody variable domain which are hypervariable in sequence (“complementarity determining regions” or “CDRs”) and / or form structurally defined loops (“hypervariable loops”) and / or contain the antigencontacting residues (“antigen contacts”). Generally, antibodies comprise six HVRs: three in the VH (H1 , H2, H3), and three in the VL (L1 , L2, L3). Exemplary HVRs herein include: (a) hypervariable loops occurring at amino acid residues 26-32 (L1 ), 50-52 (L2), 91 -96 (L3), 26-32 (H1 ), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901 -917 (1987)); (b) CDRs occurring at amino acid residues 24- 34 (L1 ), 50-56 (L2), 89-97 (L3), 31 -35b (H1 ), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991 )); (c) antigen contacts occurring at amino acid residues 27c-36 (L1 ), 46-55 (L2), 89-96 (L3), 30- 35b (H1 ), 47-58 (H2), and 93-101 (H3) (MacCallum et al., J. Mol. Biol. 262: 732-745 (1996)); and (d) combinations of (a), (b), and / or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1 ), 26-35b (H1 ), 49-65 (H2), 93-102 (H3), and 94-102 (H3). Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0122] As used herein, the term “isolated antibody” refers to an antibody which has been separated from a component of its natural environment. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. 8848:79- 87 (2007).

[0123] As used herein, the term “monoclonal antibody” or “mAb” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. , the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.

[0124] As used herein, the terms “anti-CD3 antibody” and “an antibody that binds to CD3” refer to an antibody that is capable of binding CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD3. In one embodiment, the extent of binding of an anti- CD3 antibody to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD3 has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain embodiments, an anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

[0125] As used herein, the term “CCR8” refers to any native CCR8 from any vertebrate source, including mammals such as primates (e.g., humans, monkeys (cyno)), and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses full-length, unprocessed CCR8 as well as any form of CCR8 that results from processing in the cell. The term also encompasses naturally occurring variants of CCR8, e.g., splice variants or allelic variants. In certain aspects, the CCR8 is a human CCR8 (“hCCR8” or “huCCR8”). The amino acid sequence of an exemplary human CCR8 is set forth in SEQ ID NO: 22, as shown in the below Table 1 . In certain aspects, the CCR8 is a cynomolgus monkey (“cyno”) CCR8. The amino acid sequence of an exemplary cyno CCR8 is set forth in SEQ ID NO: 23, as shown in the below Table 1. In certain aspects, the CCR8 is a mouse CCR8 (“mCCR8”). The amino acid sequence of an exemplary mouse CCR8 is set forth in SEQ ID NO: 24, as shown in the below Table 1 .

[0126] Table 1. Exemplary CCR8 sequences

[0127] As used herein, the term “cluster of differentiation 3” or “CD3” refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, including, for example, CD3e, CD3y, CD3a, and CD3p chains. The term encompasses full-length, unprocessed CD3 (e.g., unprocessed or unmodified CD3e or CD3y), as well as any form of CD3 that results from processing in the cell. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, human CD3e protein (NCBI RefSeq No. NP_000724), which is 207 amino acids in length, and human CD3y protein (NCBI RefSeq No. NP_000064), which is 182 amino acids in length.

[0128] As used herein, the terms “anti-CCR8 antibody” and “an antibody that binds to CCR8” refer to an antibody that is capable of binding CCR8 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CCR8. In one embodiment, the extent of binding of an anti-CCR8 antibody to an unrelated, non-CCR8 protein is less than about 10% of the binding of the antibody to CCR8 as measured, e.g., by surface plasmon resonance (SPR). In certain embodiments, an antibody that binds to CCR8 has a KD of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or

[0129] < 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain embodiments, an anti-CCR8 antibody binds to an epitope of CCR8 that is conserved among CCR8 from different species.

[0130] As used herein, the terms “anti-CCR8 / anti-CD3 bispecific antibody,” “bispecific anti-CCR8 / anti- CD3 antibody,” and “antibody that binds to CCR8 and CD3,” or variants thereof, refer to a multispecific antibody (e.g., a bispecific antibody) that is capable of binding to CCR8 and CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CCR8 and / or CD3. In one embodiment, the extent of binding of an anti-CCR8 / anti-CD3 bispecific antibody to an unrelated, non-CD3 protein and / or non-CCR8 protein is less than about 10% of the binding of the antibody to CD3 and / or CCR8 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CCR8 and CD3 has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM,

[0131] < 0.01 nM, or < 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, or e.g., from 10-9M to 10-13M). In certain embodiments, an anti-CCR8 / anti-CD3 bispecific antibody binds to an epitope of CD3 that is conserved among CD3 from different species and / or an epitope of CCR8 that is conserved among CCR8 from different species.

[0132] As used herein, the term “binds,” “specifically binds to,” or is “specific for” refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules. For example, an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and / or with greater duration than it binds to other targets. In one embodiment, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, for example, by a radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, or < 0.1 nM. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved among the protein from different species. In another embodiment, specific binding can include, but does not require, exclusive binding. The term as used herein can be exhibited, for example, by a molecule having a KD for the target of 10-4M or lower, alternatively 10-5M or lower, alternatively 10-6M or lower, alternatively 10-7M or lower, alternatively 10-8M or lower, alternatively 10-9M or lower, alternatively 10-10M or lower, alternatively 10-11M or lower, alternatively 10-12M or lower, or a KD in the range of 10-4M to 10-6M or 10-6M to 10'10M or 10'7M to 109M. As is appreciated by the skilled artisan, affinity and KD values are inversely related. A high affinity for an antigen is measured by a low KD value. In one embodiment, the term “specific binding” refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0133] As used herein, “percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN™ (DNASTAR®) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX® operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as 100 times the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It is appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B does not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0134] As used herein, the term “pharmaceutical formulation” or “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0135] As used herein, the term “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. As used herein, the term “chemotherapeutic agent” refers to a compound useful in the treatment of a cell proliferative disorder (e.g., NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, or HCC). Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech / OSI Pharm.); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4- morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’- Chloro-4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6- amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1 - methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4- [(1 -phenylethyl)amino]-1 H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1 - phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6- quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6- quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271 ; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4- [(3 fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4- quinazolinamine)); a tyrosine kinase inhibitor (e.g., an EGFR inhibitor; a small molecule HER2 tyrosine kinase inhibitor such as TAK165 (Takeda); CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 (ISIS Pharmaceuticals) which inhibit Raf-1 signaling; non-HER-targeted tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC®, Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI- 1040 (Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner- Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Patent No. 5,804,396); tryphostins (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521 ; Isis / Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1 C1 1 (Imclone); and rapamycin (sirolimus, RAPAMUNE®)); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasunate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafamib (SCH 66336); sorafenib (NEXAVAR®, Bayer Labs); AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1 -TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin y1 and calicheamicin w1 ); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L- norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); thiotepa; chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP- 16); ifosfamide; mitoxantrone; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above. Chemotherapeutic agents also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; (ix) growth inhibitory agents including vincas (e.g., vincristine and vinblastine), NAVELBINE® (vinorelbine), taxanes (e.g., paclitaxel, nab- paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin), and DNA alkylating agents (e.g., tamoxigen, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0136] As used herein, the term “programmed death ligand 1 ” or “PD-L1 ” refers to native sequence human PD-L1 polypeptide. Native sequence PD-L1 polypeptides are provided under Uniprot Accesion No. Q9NZQ7. For instance, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-1 (isoform 1 ). In another instance, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-2 (isoform 2). In yet another instance, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-3 (isoform 3). PD-L1 is also referred to in the art as “programmed cell death 1 ligand 1 ,” “PDCD1 LG1 ,” “CD274,” “B7-H,” and “PDL1 .”

[0137] As used herein, the term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and / or B7-1 . In some instances, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and / or B7-1 . In some instances, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1 . In one instance, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-L1 binding antagonist binds to PD-L1 . In some instances, a PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). In a preferred aspect, the PD-L1 binding antagonist (e.g., anti-PD-L1 antibody) is atezolizumab.

[0138] As used herein, the term “atezolizumab” refers to an Fc-engineered, humanized, nonglycosylated IgG 1 kappa immunoglobulin that binds PD-L1 . Atezolizumab comprises a single amino acid substitution (asparagine to alanine) at position 297 on the heavy chain (N297A) using EU numbering of Fc region amino acid residues, which results in a non-glycosylated antibody that has minimal binding to Fc receptors. Atezolizumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances (proposed INN)) List 1 12, Vol. 28, No. 4, 2014, p. 488.

[0139] As used herein, the term “cytotoxic agent” refers to a substance that inhibits or prevents a cellular function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g.,211At,131l,125l,90Y,186Re,188Re,153Sm,212Bi,32P,212Pb and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, or vinca alkaloids (vincristine, vinblastine, or etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; and the various antitumor or anticancer agents disclosed below.

[0140] As used herein, the term “effector functions” refers to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1 q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibodydependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0141] As used herein, an “effective amount” of a compound, for example, an anti-CCR8 / anti-CD3 bispecific antibody and / or a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) or a composition (e.g., pharmaceutical composition) thereof, is at least the minimum amount required to achieve the desired therapeutic result, such as a measurable improvement of a particular disorder (e.g., a cell proliferative disorder, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others). An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e. , slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and / or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0142] As used herein, the term “cytokine release syndrome” (abbreviated as “CRS”) refers to an increase in the levels of cytokines, particularly tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-y), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-2 (IL-2) and / or interleukin-8 (IL-8), in the blood of a subject during or shortly after administration of a therapeutic agent, resulting in adverse symptoms. The incidence and severity of CRS typically decrease with subsequent infusions. In some instances, e.g., after the administration of CAR-T cells, CRS can also occur only later, e.g., several days after administration upon expansion of the CAR-T cells. Symptoms may range from symptomatic discomfort to fatal events, and may include fever, chills, dizziness, hypertension, hypotension, dyspnea, restlessness, sweating, flushing, skin rash, tachycardia, tachypnoea, headache, tumor pain, nausea, vomiting and / or organ failure. A skilled artisan should recognize that CRS can be graded by a number of different published CRS grading systems, including, but not limited to, those outlined in the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading Criteria (Lee et al., Biol. Blood Marrow Transplant. 25(4):625-638 (2019)), the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03, the NCI CTCAE v5.0, and the Lee Criteria (Lee et al., Blood 124(2): 188- 195 (2014)). Unless otherwise specified, CRS grading herein follows the ASTCT Consensus Grading Criteria.

[0143] As used herein, the term “immune cell PD-L1 expression” or “IC PD-L1 expression” refers to the expression status of PD-L1 within a population of immune cells as determined by an assay (e.g., a molecular assay or an imaging assay, such as immunohistochemistry (IHC)) . In a preferred embodiment, the term refers to the percentage of PD-L1 -positive tumor-infiltrating immune cell area within the total area of a tumor sample as determined by IHC analysis of the tumor sample.

[0144] As used herein, the term “tumor cell PD-L1 expression” or “TC PD-L1 expression” refers to the expression status of PD-L1 within a population of tumor cells as determined by an assay (e.g., a molecular assay or an imaging assay, such as immunohistochemistry (IHC)). In a preferred embodiment, the term refers to the percentage of PD-L1 -positive cell area within the total area of a tumor sample as determined by IHC analysis of the tumor sample.

[0145] As used herein, the term “combined TC / IC PD-L1 expression” refers to the combined expression status of PD-L1 in the tumor cells and immune cells within a tumor sample as determined by an assay (e.g., a molecular assay or an imaging assay). In some embodiments, the combined TC / IC PD-L1 expression of a tumor sample is determined as tumor area positivity (TAP), combined positive score (CPS), or tumor proportion score (TPS) for PD-L1 in the tumor sample. In some embodiments, TAP score is based on visual estimation of the area covered by PD-L1 positive TC / IC relative to the total tumor area. In some embodiments, TPS score is the number of PD-L1 positive TC divided by the total viable tumor cells multiplied by 100. In some embodiments, CPS score is the number of PD-L1 positive TC / IC, divided by the total number of viable tumor cells multiplied by 100.

[0146] As used herein, the term “targetable somatic alteration” refers to genetic alterations (e.g., chromosomal abnormalities and gene alterations, such as mutations) in somatic cells that can be specifically targeted by a therapeutic. Exemplary somatic alterations are known in the art and can be found, e.g., in Choi et al. Int. J. Mol. Sci. 24(17):13618 (2023). In some embodiments, the targetable somatic alteration comprises a somatic alteration involving epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1 ), proto-oncogene B-Raf (BRAF) V600E, neurotrophic tyrosine receptor kinase (NTRK), MET proto-oncogene (MET), RET proto-oncogene (RET), or Kirsten rat sarcoma virus (KRAS).

[0147] As used herein, the term “BRAFV600 mutation” refers to a mutation or deletion of the valine amino acid residue at position 600 of the gene BRAF. Exemplary BRAFV600 mutations include the V600E, V600K, V600R, and V600D mutations, and can be found, e.g., in Ascierto et al. J. Transl. Med. 10:85 (2012).

[0148] As used herein, the term “disease progression” refers to the appearance of new evidence of advancement or worsening of an existing disease by a diagnostic assay (e.g., a molecular assay or an imaging assay). For example, a cancer patient experiencing disease progression may have increased tumor size or development of metastasis of existing tumors.

[0149] As used herein, the term “intolerance to treatment” refers to a subject’s inability to tolerate the side effects (e.g., adverse effects such as toxicity) of a treatment regimen or therapeutic. Intolerance to treatment often necessitates reduced dosage or dosing frequency, delayed treatment, or alteration of treatment regimen or therapeutic.

[0150] As used herein, the term “serine / threonine-protein kinase B-Raf inhibitor” or “BRAF inhibitor” refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with BRAF activation or function. Examples of BRAF inhibitors include, without limitation, vemurafenib (ZELBORAF®), dabrafenib, encorafenib (LGX818), GDC-0879, XL281 , ARQ736, PLX3603, RAF265, and sorafenib, or a pharmaceutically acceptable salt thereof. BRAF inhibitors may inhibit only BRAF or may inhibit BRAF and one or more additional targets. Preferred BRAF inhibitors are described in PCT Application Publication Nos. WO 2005 / 062795, WO 2007 / 002325, WO 2007 / 002433, WO 2008 / 079903, and WO 2008 / 079906, each of which is incorporated herein by reference in its entirety.

[0151] As used herein, the term “mitogen-activated protein kinase kinase inhibitor” or “MEK inhibitor” refers to molecule that decreases, blocks, inhibits, abrogates, or interferes with MEK (e.g., MEK1 and / or MEK2) activation or function. Examples of MEK inhibitors include, without limitation, cobimetinib (e.g., cobimetinib hemifumarate; COTELLIC®), trametinib, binimetinib, selumetinib, pimasertinib, refametinib, G DC-0623, PD-0325901 , and BI-847325, or a pharmaceutically acceptable salt thereof. MEK inhibitors may inhibit only MEK or may inhibit MEK and one or more additional targets. Preferred MEK inhibitors are described in PCT Application Publication Nos. WO 2007 / 04451 5, WO 2008 / 024725, WO 2008 / 024724, WO 2008 / 067481 , WO 2008 / 1 57179, WO 2009 / 085983, WO 2009 / 085980, WO 2009 / 082687, WO 2010 / 003025, and WO 2010 / 003022, each of which is incorporated herein by reference in its entirety.

[0152] As used herein, the term “bispecific antibody-CCR8 receptor-CD3 trimer” or “trimer” refers to the complex formed between an anti-CCR8 / anti-CD3 bispecific antibody, a CCR8 receptor, and a CD3 molecule. In some embodiments, the CCR8 receptor is on a CCR8-expressing cell. In a preferred embodiment, the CCR8-expressing cell is a CCR8+ Treg cell. A CCR8-expressing cell can have more than one bispecific antibody-CCR8 receptor-CD3 trimers formed on its surface, because it is possible for such a cell to have more than one CCR8 receptor on its surface. In some embodiments, the CD3 molecule is on a CD3-expressing cell. In a preferred embodiment, the CD3-expressing cell is a CD8+ T cell. A CD3-expressing cell can have more than one bispecific antibody-CCR8 receptor-CD3 trimers formed on its surface, because it is possible for such a cell to have more than one CD3 molecule on its surface.

[0153] III. Therapeutic Methods

[0154] A. Therapeutic Methods for Treating Cell Proliferative Disorders

[0155] The methods provided herein benefit patients by providing methods of treating cell proliferative disorders while achieving a more favorable benefit-risk profile. Thus, provided herein are methods for treating a subject having a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others) by administering an effective amount of a bispecific antibody that binds CCR8 and CD3 alone or in combination with a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) in a multi-cycle dosing regimen, optionally involving a fractionated, escalating dose of the bispecific antibody in the first dosing cycle.

[0156] In some aspects, the invention provides methods for treating a subject having a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others) that includes administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 in a dosing regimen comprising one or more dosing cycles, in which each of the one or more dosing cycles comprises one or more doses of the bispecific antibody that binds CCR8 and CD3, and, optionally, one or more doses of a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab).

[0157] In some instances, the invention involves treating a subject having a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others) by administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 0.9 mg (e.g., about 0.1 mg, about 0.45 mg, or about 0.9 mg). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.1 mg, about 0.45 mg, or about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.1 mg, about 0.45 mg, or about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 1 .8 mg, about 100 mg, or about 300 mg.

[0158] In some embodiments, the first dosing cycle is about 21 days. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the first dosing cycle.

[0159] In some embodiments, the dosing regimen comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to six (e.g., one, two, three, four, five, or six) additional dosing cycles. In some embodiments, the dosing regimen comprises one to 20 (e.g., one, two, three, four, five, six, seven, eighteen, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) additional dosing cycles.

[0160] In some embodiments, the length of each of the one or more additional dosing cycles is about 21 days. In some embodiments, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some embodiments, each single dose of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 1 of the bispecific antibody. In some embodiments, each single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0161] In some instances, the invention involves treating a subject having a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others) by administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (Cycle 1 , Dose 1) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher in amount than the Cycle 1 , Dose 1 of the bispecific antibody; and (b) the second dosing cycle comprises a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 0.9 mg (e.g., about 0.1 mg, about 0.45 mg, or about 0.9 mg). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 1 .8 mg, about 100 mg, or about 300 mg. In some embodiments, the Cycle 1 , Dose 2 of the bispecific antibody is about 3 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg.

[0162] In some embodiments, the length of the first dosing cycle is about 21 days. In some embodiments, the Cycle 1 , Dose 1 and the Cycle 1 , Dose 2 of the bispecific antibody are administered to the subject on about Day 1 and about Day 8, respectively, of the first dosing cycle. In some embodiments, the length of the second dosing cycle is about 21 days. In some embodiments, the Cycle 2, Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the second dosing cycle.

[0163] In some embodiments, the dosing regimen comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to six (e.g., one, two, three, four, five, or six) additional dosing cycles. In some embodiments, the dosing regimen comprises one to 20 (e.g., one, two, three, four, five, six, seven, eighteen, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) additional dosing cycles.

[0164] In some embodiments, the length of each of the one or more additional dosing cycles is about 21 days. In some embodiments, the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some embodiments, each single dose of the bispecific antibody is about equivalent in amount to the Cycle 2, Dose 1 of the bispecific antibody. In some embodiments, each single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0165] In some instances, the invention involves treating a subject having a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others) by administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 and an effective amount of a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises: (a) a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody; and (b) a single dose (Cycle 1 , Dose 1 ) of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 0.9 mg (e.g., about 0.1 mg, about 0.45 mg, or about 0.9 mg). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 1 .8 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the PD-L1 binding antagonist is atezolizumab. In some embodiments, the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg.

[0166] In some embodiments, the length of the first dosing cycle is about 21 days. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the first dosing cycle. In some embodiments, the Cycle 1 , Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of the first dosing cycle. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody and the Cycle 1 , Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in the first dosing cycle.

[0167] In some embodiments, the dosing regimen comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to six (e.g., one, two, three, four, five, or six) additional dosing cycles. In some embodiments, the dosing regimen comprises one to 20 (e.g., one, two, three, four, five, six, seven, eighteen, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) additional dosing cycles.

[0168] In some embodiments, the length of each of the one or more additional dosing cycles is about 21 days. In some embodiments, each of the one or more additional dosing cycles comprises: (a) a single dose of the bispecific antibody; and (b) a single dose of the PD-L1 binding antagonist (e.g., the anti-PD- L1 antibody; e.g., atezolizumab). In some embodiments, each single dose of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 1 of the bispecific antibody. In some embodiments, the PD-L1 binding antagonist is atezolizumab. In some embodiments, each single dose of atezolizumab is about 1200 mg. In some embodiments, the single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles. In some embodiments, the single dose of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of each of the one or more additional dosing cycles. In some embodiments, the single dose of the bispecific antibody and the single dose of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in each of the one or more additional dosing cycles.

[0169] In some instances, the invention involves treating a subject having a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others) by administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 and an effective amount of a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises: (i) a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher than the Cycle 1 , Dose 1 of the bispecific antibody; and (ii) a single dose (Cycle 1 , Dose 1 ) of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab); and (b) the second dosing cycle comprises: (i) a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody; and (ii) a single dose (Cycle 2, Dose 1 ) of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 0.9 mg (e.g., about 0.1 mg, about 0.45 mg, or about 0.9 mg). In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is about 1 .8 mg, about 100 mg, or about 300 mg. In some embodiments, the Cycle 1 , Dose 2 of the bispecific antibody is about 3 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.1 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.45 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.45 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 100 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 1 .8 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 1 .8 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg. In some embodiments, the PD-L1 binding antagonist is atezolizumab. In some embodiments, the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg. In some embodiments, the Cycle 2, Dose 1 of atezolizumab is about 1200 mg.

[0170] In some embodiments, the length of the first dosing cycle is about 21 days. In some embodiments, the Cycle 1 , Dose 1 and the Cycle 1 , Dose 2 of the bispecific antibody are administered to the subject on about Day 1 and about Day 8, respectively, of the first dosing cycle. In some embodiments, the Cycle 1 , Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of the first dosing cycle. In some embodiments, the Cycle 1 , Dose 1 of the bispecific antibody and the Cycle 1 , Dose 1 of the PD-L1 binding antagonist (e.g., the anti- PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in the first dosing cycle. In some embodiments, the length of the second dosing cycle is about 21 days. In some embodiments, the Cycle 2, Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the second dosing cycle. In some embodiments, the Cycle 2, Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of the second dosing cycle. In some embodiments, the Cycle 2, Dose 1 of the bispecific antibody and the Cycle 2, Dose 1 of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in the second dosing cycle.

[0171] In some embodiments, the dosing regimen comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to six (e.g., one, two, three, four, five, or six) additional dosing cycles. In some embodiments, the dosing regimen comprises one to 20 (e.g., one, two, three, four, five, six, seven, eighteen, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20) additional dosing cycles.

[0172] In some embodiments, the length of each of the one or more additional dosing cycles is about 21 days. In some embodiments, each of the one or more additional dosing cycles comprises: (a) a single dose of the bispecific antibody; and (b) a single dose of the PD-L1 binding antagonist (e.g., the anti-PD- L1 antibody; e.g., atezolizumab). In some embodiments, each single dose of the bispecific antibody is about equivalent in amount to the Cycle 2, Dose 1 of the bispecific antibody. In some embodiments, the PD-L1 binding antagonist is atezolizumab. In some embodiments, each single dose of atezolizumab is about 1200 mg. In some embodiments, the single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles. In some embodiments, the single dose of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered to the subject on about Day 1 of each of the one or more additional dosing cycles. In some embodiments, the single dose of the bispecific antibody and the single dose of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered to the subject on about the same day in each of the one or more additional dosing cycles.

[0173] In some embodiments, the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) is administered intravenously. In some embodiments the bispecific antibody and the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered on about the same day, the bispecific antibody is administered after (e.g., at least 30 minutes after) the end of the administration of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab). In some embodiments, when the bispecific antibody and the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) are administered on about the same day, the bispecific antibody is administered after (e.g., at least 60 minutes after) the end of the administration of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab).

[0174] In some embodiments, the bispecific antibody is administered intravenously.

[0175] In some embodiments, the method further comprises administering to the subject an effective amount of a corticosteroid. In some embodiments, the corticosteroid is dexamethasone or methylprednisolone. In some embodiments, dexamethasone is administered at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. In some embodiments, dexamethasone is administered at a dose of about 20 mg. In some embodiments, methylprednisolone is administered at a dose of about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg. In some embodiments, methylprednisolone is administered at a dose of about 80 mg. In some embodiments, the corticosteroid is administered prior to (e.g., about one hour prior to) the administration of any dose of the bispecific antibody in the first dosing cycle. In some embodiments, when the bispecific antibody, the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab), and the corticosteroid are administered on about the same day, the corticosteroid is administered after (e.g., at least 60 minutes after) the end of the administration of the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab) and prior to (e.g., about one hour prior to) the start of the administration of the bispecific antibody. In some embodiments, the subject experiences cytokine release syndrome (CRS), infusion-related reaction (IRR), or immune effector cell-associated neurotoxicity syndrome (ICANS) in a dosing cycle, and the corticosteroid is administered prior to (e.g., about one hour prior to) the administration of the bispecific antibody in the next dosing cycle.

[0176] In some embodiments, the method further comprises administering to the subject an effective amount of tocilizumab. In some embodiments, tocilizumab is administered at a dose of about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, or about 16 mg / kg. In some embodiments, tocilizumab is administered at a dose of about 8 mg / kg. In some embodiments, each dose of tocilizumab is about 12 mg / kg. In some embodiments, the subject experiences CRS after being administered the bispecific antibody, and wherein dexamethasone is administered to the subject about every 6 hours. In some embodiments, the subject experiences CRS after being administered the bispecific antibody, and tocilizumab and dexamethasone are administered to the subject about every 6 hours. In some embodiments, dexamethasone is administered at a dose of about 10 mg; and / or wherein tocilizumab is administered at a dose of about 8 mg / kg or about 12 mg / kg. In some embodiments, tocilizumab is administered intravenously. In some embodiments, the corticosteroid is administered intravenously.

[0177] In some embodiments, the method further comprises administering to the subject an effective amount of an antihistamine. In some embodiments, the antihistamine is diphenhydramine. In some embodiments, diphenhydramine is administered at a dose of from about 25 mg to about 50 mg (e.g., from about 25 mg to about 45 mg, from about 25 mg to about 40 mg, from about 25 mg to about 35 mg, from about 25 mg to about 30 mg, from about 30 mg to about 50 mg, from about 35 mg to about 50 mg, from about 40 mg to about 50 mg, from about 45 mg to about 50 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, the antihistamine is administered prior to (e.g., at least about 30 minutes prior to) the administration of any dose of the bispecific antibody. In some embodiments, the antihistamine is administered orally.

[0178] In some embodiments, the method further comprises administering to the subject an effective amount of acetaminophen or paracetamol. In some embodiments, acetaminophen or paracetamol is administered at a dose of from about 500 mg to about 1 ,000 mg (e.g., from about 500 mg to about 900 mg, from about 500 mg to about 800 mg, from about 500 mg to about 700 mg, from about 500 mg to about 600 mg, from about 600 mg to about 1 ,000 mg, from about 700 mg to about 1 ,000 mg, from about 800 mg to about 1 ,000 mg, from about 900 mg to about 1 ,000 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1 ,000 mg). In some embodiments, acetaminophen or paracetamol is administered prior to (e.g., at least about 30 minutes prior to) the administration of any dose of the bispecific antibody. In some embodiments, acetaminophen or paracetamol is administered orally.

[0179] In some embodiments, the subject is a human.

[0180] In some embodiments, the subject (a) has progressed after at least one available standard therapy; and / or (b) is one for whom all available standard therapy has been proven to be ineffective or intolerable or is contraindicated.

[0181] In some embodiments, the subject’s age is 18 years or older. In some embodiments, the subject is checkpoint inhibitor (CPI)-naTve. In some embodiments, the cell proliferation disorder is NSCLC, and wherein the subject has a tumor cell (TC) PD-L1 expression of > 50%, or an immune cell (IC) PD-L1 expression of > 10%. In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a combined TC / IC PD-L1 expression of > 20. In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a combined TC / IC PD-L1 expression of > 1 and < 19. In some embodiments, the combined TC / IC PD-L1 expression is determined as tumor area positivity (TAP) or combined positive score (CPS). In some embodiments, TAP score is based on visual estimation of the area covered by PD-L1 positive TC / IC relative to the total tumor area. In some embodiments, CPS score is the number of PD-L1 positive TC / IC, divided by the total number of viable tumor cells multiplied by 100. In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 20%. In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 5% to > 19%.

[0182] In some embodiments, the subject is CPI-experienced. In some embodiments, the cell proliferation disorder is NSCLC, HNSCC, gastric cancer, GEJ adenocarcinoma, HCC, ccRCC, TNBC, or UCC, and wherein the subject has a TC, IC, or combined TC / IC PD-L1 expression of > 1 or 1%. In some embodiments, the cell proliferation disorder is esophageal cancer, and wherein the subject has a TC, IC, or combined TC / IC PD-L1 expression of > 10 or 10%. In some embodiments, the combined TC / IC PD-L1 expression is determined as CPS, TAP, or tumor proportion score (TPS). In some embodiments, TPS score is the number of PD-L1 positive TC divided by the total viable tumor cells multiplied by 100. In some embodiments, the cell proliferation disorder is NSCLC, and wherein the subject has an IC PD-L1 expression of > 1%. In some embodiments, the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 5%. In some embodiments, the cell proliferation disorder is gastric cancer or GEJ adenocarcinoma, and wherein the subject has a PD-L1 TAP of > 1%. In some embodiments, the cell proliferation disorder is ccRCC, TNBC, or UCC, and wherein the subject has an IC PD-L1 expression of > 1%. In some embodiments, the cell proliferation disorder is esophageal cancer, and wherein the subject has a PD-L1 TAP of > 10%.

[0183] In some embodiments, the subject’s tumor comprises a targetable somatic alteration, and the subject has experienced disease progression during or after treatment, or intolerance to treatment, with a targeted agent. In some embodiments, the targetable somatic alteration comprises a somatic alteration involving epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS protooncogene 1 (ROS1 ), proto-oncogene B-Raf (BRAF) V600E, neurotrophic tyrosine receptor kinase (NTRK), MET proto-oncogene (MET), RET proto-oncogene (RET), or Kirsten rat sarcoma virus (KRAS). In some embodiments, the cell proliferation disorder is cutaneous melanoma, wherein the subject’s tumor comprises a BRAFV600 mutation, and wherein the subject has experienced disease progression during or after treatment, or intolerance to treatment, with one or more serine / threonine-protein kinase B-Raf (BRAF) inhibitors and / or one or more mitogen-activated protein kinase kinase (MEK) inhibitors.

[0184] In some embodiments, the cell proliferative disorder is NSCLC. In some embodiments, the cell proliferative disorder is HNSCC. In some embodiments, the HNSCC is HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx. In some embodiments, the cell proliferative disorder is a cancer. In some embodiments, the cell proliferative disorder is a solid tumor malignancy. In some embodiments, the cell proliferative disorder is a locally advanced, recurrent, or metastatic incurable solid tumor malignancy. In some embodiments, the cell proliferative disorder is selected from the group consisting of NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC.

[0185] B. Methods for Assessing PD-L1 Expression

[0186] In some instances, the method further comprises determining the expression level of programmed death-ligand 1 (PD-L1 ) in a sample obtained from the subject. In some embodiments, the sample is a tumor sample. In some embodiments, the sample is a fresh tumor sample, a formalin-fixed, paraffin-embedded tumor sample, or an archival tumor sample. In some embodiments, the sample comprises tumor cells, tumor infiltrating immune cells, stromal cells, and any combinations thereof. In some embodiments, the sample is obtained prior to the first dosing cycle. In some embodiments, PD-L1 is absent from the sample when it comprises 0% of the sample. In some embodiments, PD-L1 is present in the sample when it comprises more than 0% of the sample. In some embodiments, PD-L1 is expressed in tumor cells covering at least 1% (e.g., at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%) of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor cells covering at least 5% of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor cells covering at least 10% of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor cells covering at least 20% of the tumor sample area. In some embodiments, PD- L1 is expressed in tumor cells covering at least 50% of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor-infiltrating immune cells covering at least 1% (e.g., at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15%) of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor-infiltrating immune cells covering at least 5% of the tumor sample area. In some embodiments, PD-L1 is expressed in tumor-infiltrating immune cells covering at least 10% of the tumor sample area.

[0187] The expression of PD-L1 may be assessed in a patient treated according to any of the methods and compositions for use described herein. The methods and compositions for use may include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the patient. In other instances, the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the patient has been determined prior to initiation of treatment or after initiation of treatment. PD-L1 expression may be determined using any suitable approach. For instance, PD-L1 expression may be determined as described in U.S. Patent Application Nos. 15 / 787,988 and 15 / 790,680. Any suitable tumor sample may be used, e.g., a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample.

[0188] For instance, PD-L1 expression may be determined in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of PD-L1 , as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of PD-L1 , as the percentage of tumor cells in a tumor sample expressing a detectable expression level of PD-L1 , and / or as the percentage of tumor cells and immune cells expressing a detectable expression level of PD-L1 in a tumor sample. It is to be understood that in any of the preceding instances, the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the patient, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., the SP142 antibody). Any suitable anti-PD-L1 antibody may be used, including, e.g., SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1 L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11. In some instances, the anti-PD-L1 antibody is SP142. In other instances, the anti-PD-L1 antibody is SP263.

[0189] In some instances, a tumor sample obtained from the patient has a detectable expression level of PD-L1 in less than 1 % of the tumor cells in the tumor sample, in 1 % or more of the tumor cells in the tumor sample, in from 1% to less than 5% of the tumor cells in the tumor sample, in 5% or more of the tumor cells in the tumor sample, in from 5% to less than 50% of the tumor cells in the tumor sample, or in 50% or more of the tumor cells in the tumor sample.

[0190] In some instances, a tumor sample obtained from the patient has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise less than 1% of the tumor sample, more than 1% of the tumor sample, from 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, from 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.

[0191] In some instances, a tumor sample obtained from the patient has a detectable expression level of PD-L1 in tumor-infiltrating immune cells and tumor cells as defined as TAP, TPS, or CPS scores that comprise less than 1% of the tumor sample or cells, more than 1% of the tumor sample or cells, from 1% to less than 5% of the tumor sample or cells, more than 5% of the tumor sample or cells, from 5% to less than 20% of the tumor sample or cells, more than 20% of the tumor sample or cells, less than 10% of the tumor sample or cells, or more than 10% of the tumor sample or cells.

[0192] In some instances, tumor samples may be scored for PD-L1 positivity in tumor-infiltrating immune cells and / or in tumor cells according to the criteria for diagnostic assessment shown in Table 2 and / or Table 3, respectively.

[0193] Table 2. Tumor-Infiltrating Immune Cell (IC) IHC Diagnostic Criteria

[0194] Table 3. Tumor Cell (TC) IHC Diagnostic Criteria

[0195] IV. Therapeutic Agents for Use in the Methods of the Invention

[0196] A. Anti-CCR8 / Anti-CD3 Bispecific Antibodies a. Summary

[0197] In some instances, the methods described herein include administering an effective amount of the anti-CCR8 / anti-CD3 bispecific antibody to a subject having a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others). In some instances, the anti-CCR8 / anti-CD3 bispecific antibody eliminates CCR8+ Treg cells (e.g., CCR9+ Treg cells in the tumor microenvironment of a cancer) through T cell-mediated depletion, thus reversing the suppression of effector T cells (e.g., CD8+ or CD4+ effector T cells) by said Treg cells and enhancing anti-tumor immunity.

[0198] The anti-CCR8 / anti-CD3 bispecific antibody (also referred to as the “anti-CCR8 / CD3 TDB,” “CCR8 TDB,” “TDB,” or “RO7759065”) is a bispecific antibody with two Fabs binding to CCR8 and one Fab binding to CD3. In some embodiments, the anti-CCR8 / anti-CD3 bispecific antibody is a humanized IgG 1 antibody. In some embodiments, the anti-CCR8 / anti-CD3 bispecific antibody is produced in Chinese hamster ovary (CHO) cells. In some embodiments, the anti-CCR8 / anti-CD3 bispecific antibody consists of two heavy chains and three light chains. b. Physical and Chemical Properties

[0199] The anti-CCR8 / anti-CD3 bispecific antibody is a 2 + 1 format bispecific antibody with two Fabs binding to human and cynomolgus monkey CCR8 and one Fab binding to human and cynomolgus monkey CD3. Heterodimerization of the two heavy chains is driven by “knob” and “hole” mutations of the CH3 domain of the Fc region. To promote selective pairing of cognate heavy and light chains, charge-pair modifications in the Fab arms are located at the variable fragment heavy chain-variable fragment light chain (VH-VL) interface outside of the CDRs and at the CH1 -CL interface. The anti-CCR8 / anti-CD3 bispecific antibody contains LALAPG mutations (i.e. , L234A, L235A and P329G amino acid substitution) in the Fc region to impair binding to Fey receptors and attenuate Fc effector function. The light chain of the CCR8-binding Fab also contains a S12P amino acid substitution to facilitate removal of unwanted product variants during the manufacturing process. The physical and chemical properties of the anti- CCR8 / anti-CD3 bispecific antibody are presented in Table 4.

[0200] Table 4. Physical and Chemical Properties of the Anti-CCR8 / Anti-CD3 Bispecific Antibody c. Structural Properties

[0201] In one aspect, the present disclosure provides bispecific antigen-binding molecules (e.g., bispecific antibodies; e.g., anti-CCR8 / anti-CD3 bispecific antigen-binding molecules; e.g., anti-CCR8 / anti- CD3 bispecific antibodies) bind to CCR8 and CD3. In one aspect, the bispecific antigen-binding molecules provided are isolated bispecific antigen-binding molecules that bind to CD3 and CCR8. In one aspect, the present disclosure provides bispecific antigen-binding molecules that include one or more antigen-binding moieties that specifically bind to a Treg cell antigen (e.g., CCR8) and one or more antigen-binding moieties that specifically bind to an activating T cell antigen (e.g., CD3). In one aspect, the present disclosure provides bispecific antigen-binding molecules that include one or more antigenbinding moieties that specifically bind to CCR8 and one or more antigen-binding moieties that specifically bind to CD3. In one aspect, the present disclosure provides bispecific antigen-binding molecules that include two antigen-binding moieties that specifically bind to CCR8 and one antigen-binding domain that specifically bind to CD3. In certain aspects, the CCR8 is a human CCR8. In certain aspects, the CD3 is a human CD3 or a cynomolgus monkey (cyno) CD3. In one aspect, the invention provides isolated bispecific antigen-binding molecules that bind to CCR8 and CD3. In some embodiments, an antigen-binding domain of the bispecific antigen-binding molecule of the present invention comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs (e.g., comprises one, two, three, four, five, or six CDRs) as illustrated in Table 5 (Kabat). In some instances, the antigen-binding molecule comprises a VH and / or a VL as illustrated in Table 5.

[0202] Table 5. Listing of CDR and Variable Domain (V) Sequences of Anti-CCR8 / Anti-CD3 Bispecific Antibodies

[0203] In some aspects, the invention provides a bispecific antibody comprising: (a) a first antigenbinding domain that binds CCR8, wherein the first antigen-binding domain comprises the following six CDRs: (i) a CDR-H1 comprising the amino acid sequence TYAMG (SEQ ID NO: 1 ); (ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO: 2); (iii) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3); (iv) a light chain complementarity-determining region 1 (CDR-L1 ) comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4); (v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and (vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6); (b) a second antigen-binding domain that binds cluster of differentiation 3 (CD3), wherein the second antigen-binding domain comprises the following six CDRs: (i) a CDR-H1 comprising the amino acid sequence NYYIH (SEQ ID NO: 7); (ii) a CDR-H2 comprising the amino acid sequence WIYPGDGNTKYNEKFKG (SEQ ID NO: 8); (iii) a CDR-H3 comprising the amino acid sequence DSYSNYYFDY (SEQ ID NO: 9); (iv) a CDR-L1 comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 10); (v) a CDR-L2 comprising the amino acid sequence WASTRES (SEQ ID NO: 11 ); and (vi) a CDR-L3 comprising the amino acid sequence TQSFILRT (SEQ ID NO: 12); and (c) a third antigen-binding domain that binds CCR8, wherein the third antigen-binding domain comprises the following six CDRs: (i) a CDR-H1 comprising the amino acid sequence TYAMG (SEQ ID NO: 1 ); (ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO: 2); (iii) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3); (iv) a CDR-L1 comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4); (v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and (vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6). In some aspects, the first antigen-binding domain is CCR8 1189 S12P (P), the second antigen-binding domain is CD3 40G5c, and the third antigen-binding domain is CCR8 1189 S12P (P). In some embodiments, the first antigen-binding domain comprises a light chain variable region (VL) domain and a heavy chain variable region (VH) domain, and wherein: (a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); and / or (b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat). In some embodiments, the first antigen-binding domain comprises a VL domain and a VH domain, and wherein: (a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); (b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat); or (c) the VL domain comprises a proline residue at position 12 (numbering according to Kabat) and the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat). In some embodiments, the second antigen-binding domain comprises a VL domain and a VH domain, and wherein the VL domain comprises a glutamic acid residue at position 38 and the VH domain comprises a lysine residue at position 39 (numbering according to Kabat). In some embodiments, the third antigen-binding domain comprises a VL domain and a VH domain, and wherein: (a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); and / or (b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat). In some embodiments, the third antigen-binding domain comprises a VL domain and a VH domain, and wherein: (a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); (b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat); or (c) the VL domain comprises a proline residue at position 12 (numbering according to Kabat) and the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat).

[0204] In some embodiments, (a) the first antigen-binding domain comprises one or more of the following eight framework regions (FRs): (i) an FR-H1 comprising the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAASGIDLS (SEQ ID NO: 25); (ii) an FR-H2 comprising the amino acid sequence of WVREAPGKGLEWVG (SEQ ID NO: 26); (iii) an FR-H3 comprising the amino acid sequence of RFTISKDSSKNTLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 27); (iv) an FR-H4 comprising the amino acid sequence of WGQGTTVTVSS (SEQ ID NO: 28); (v) an FR-L1 comprising the amino acid sequence of DIQVTQSPSSLPASVGDRVTITC (SEQ ID NO: 29); (vi) an FR-L2 comprising the amino acid sequence of WYQKKPGKPPKFLIY (SEQ ID NO: 30); (vii) an FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTFTISSLQPEDIATYYC (SEQ ID NO: 31 ); and / or (viii) an FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 32); (b) the second antigen-binding domain comprises one or more of the following eight FRs: (i) an FR-H1 comprising the amino acid sequence of EVQLVQSGAEVKKPGASVKVSCKASGYTFT (SEQ ID NO: 33); (ii) an FR-H2 comprising the amino acid sequence of WVRKAPGQGLEWIG (SEQ ID NO: 34); (iii) an FR-H3 comprising the amino acid sequence of RATLTADTSTSTAYLELSSLRSEDTAVYYCAR (SEQ ID NO: 35); (iv) an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 36); (v) an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 37); (vi) an FR-L2 comprising the amino acid sequence of WYQEKPGQPPKLLIY (SEQ ID NO: 38); (vii) an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 39); and / or (viii) an FR-L4 comprising the amino acid sequence of FGQGTKVEIK (SEQ ID NO: 40); and / or (c) the third antigen-binding domain comprises one or more of the following eight FRs: (i) an FR-H1 comprising the amino acid sequence of SEQ ID NO: 25; (ii) an FR-H2 comprising the amino acid sequence of SEQ ID NO: 26; (iii) an FR-H3 comprising the amino acid sequence of SEQ ID NO: 27; (iv) an FR-H4 comprising the amino acid sequence of SEQ ID NO: 28; (v) an FR-L1 comprising the amino acid sequence of SEQ ID NO: 29; (vi) an FR-L2 comprising the amino acid sequence of SEQ ID NO: 30; (vii) an FR-L3 comprising the amino acid sequence of SEQ ID NO: 31 ; and / or (viii) an FR-L4 comprising the amino acid sequence of SEQ ID NO: 32.

[0205] In some aspects, the first antigen-binding domain comprises:

[0206] (a) a VH domain comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAASGIDLSTYAMGWVREAPGKGLEWVGLIHRSGRTYYATWAKGRFTI SKDSSKNTLYLQMNSLRAEDTAVYYCTRSYPDYSATASIWGQGTTVTVSS (SEQ ID NO: 13);

[0207] (b) a VL domain comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of DIQVTQSPSSLPASVGDRVTITCQASENIANALAWYQKKPGKPPKFLIYGASNLASGVPSRFSGSGSGTD FTFTISSLQPEDIATYYCQQAYYGNSFVEGTFGGGTKVEIK (SEQ ID NO: 14); or

[0208] (c) a VH domain as in (a) and a VL domain as in (b).

[0209] In some aspects, the second antigen-binding domain comprises:

[0210] (a) a VH domain comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVRKAPGQGLEWIGWIYPGDGNTKYNEKFKGRA TLTADTSTSTAYLELSSLRSEDTAVYYCARDSYSNYYFDYWGQGTLVTVSS (SEQ ID NO: 15);

[0211] (b) a VL domain comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKSSQSLLNSRTRKNYLAWYQEKPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCTQSFILRTFGQGTKVEIK (SEQ ID NO: 16); or

[0212] (c) a VH domain as in (a) and a VL domain as in (b).

[0213] In some aspects, the third antigen-binding domain comprises:

[0214] (a) a VH domain comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13;

[0215] (b) a VL domain comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 14; or

[0216] (c) a VH domain as in (a) and a VL domain as in (b).

[0217] In some embodiments, the first antigen-binding domain comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 13; (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 14; or (c) a VH domain as in (a) and a VL domain as in (b); the second antigen-binding domain comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b); and / or the third antigen-binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 13; (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 14; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the first antigenbinding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14; the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 15 and a VL domain comprising the amino acid sequence of SEQ ID NO: 16; and the third antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14. In some aspects, the first antigen-binding domain is CCR8 1189 S12P (P); the second antigen-binding domain is CD3 40G5c; and the third antigen-binding domain is CCR8 1189 S12P (P).

[0218] In some aspects, the first antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain; the second antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain; and / or the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain. In some aspects, (a) the first antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain; (b) the second antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain; (c) the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain; or (d) the first antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, the second antigenbinding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, and the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain. In some embodiments, the first antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, the second antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, and the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, wherein: (a) the Fab light chain of the first antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the first antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat); (b) the Fab light chain of the second antigen-binding domain comprises a lysine residue at position 133, and the Fab heavy chain of the second antigen-binding domain comprises a glutamic acid residue at position 183 (numbering according to Kabat); and / or (c) the Fab light chain of the third antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the third antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat). In some embodiments, the first antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, the second antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, and the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, wherein: (a) the Fab light chain of the first antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the first antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat); (b) the Fab light chain of the second antigenbinding domain comprises a lysine residue at position 133, and the Fab heavy chain of the second antigen-binding domain comprises a glutamic acid residue at position 183 (numbering according to Kabat); (c) the Fab light chain of the third antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the third antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat); or (d) the Fab light chain of the first antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the first antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat) and the Fab light chain of the second antigen-binding domain comprises a lysine residue at position 133; the Fab heavy chain of the second antigen-binding domain comprises a glutamic acid residue at position 183 (numbering according to Kabat); and the Fab light chain of the third antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the third antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat).

[0219] In some aspects, the second antigen-binding domain and the third antigen-binding domain are fused to each other. In some embodiments, the second antigen-binding domain and the third antigenbinding domain are fused to each other via a peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of DKTHT (SEQ ID NO: 21 ). In some embodiments, the second antigen-binding domain and the third antigen-binding domain are each a Fab molecule, and wherein the third antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen-binding domain.

[0220] In some aspects, the bispecific antibody further comprises an Fc domain comprising a first subunit and a second subunit. In some embodiments, the Fc domain is an IgG Fc domain. Any suitable IgG Fc domain may be used, e.g., an IgGi Fc domain, an lgG2 Fc domain, an IgGs Fc domain, or an lgG4 Fc domain. In some embodiments, the Fc domain is an IgGi Fc domain. In some embodiments, the Fc domain is a human IgG Fc domain. In some embodiments, the Fc domain comprises a modification promoting the association of the first subunit and the second subunit of the Fc domain.

[0221] In some aspects, the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH2i) domain, a first CH3 (CH3i) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain. In some embodiments, the first subunit comprises one or more heavy chain constant domains selected from a first CH2 (CH2i) domain and / or a first CH3 (CH3i) domain; and the second subunit comprises one or more heavy chain constant domains selected from a second CH2 (CH22) domain and / or a second CH3 (CH32) domain. In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some embodiments, the CH3i and CH32 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3i domain is positionable in the cavity or protuberance, respectively, in the CH32 domain. In some embodiments, the CH3i and CH32 domains meet at an interface between said protuberance and cavity. In some embodiments, the CH2i and CH22 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2i domain is positionable in the cavity or protuberance, respectively, in the CH22 domain. In some embodiments, the CH2i and CH22 domains meet at an interface between said protuberance and cavity.

[0222] In some aspects, the first antigen-binding domain and the second antigen-binding domain are each a Fab molecule and the bispecific antibody comprises an Fc domain comprising a first subunit and a second subunit; and wherein the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit and the second antigen-binding domain is fused at the C- terminus of the Fab heavy chain to the N-terminus of the second subunit.

[0223] In some aspects, the first subunit comprises a tryptophan residue at position 366; and the second subunit comprises a serine residue at position 366, an alanine residue at position 368, and a valine residue at position 407 (numbered according to Kabat EU index).

[0224] In some aspects, each of the first subunit and the second subunit comprises an alanine residue at position 234, an alanine residue at position 235, and a glycine residue at position 329 (numbering according to Kabat EU index).

[0225] In some aspects, the bispecific antibody comprises an Fc domain comprising of a first subunit and a second subunit; wherein the first antigen-binding domain, the second antigen-binding domain, and the third antigen-binding domain are each a Fab molecule; wherein the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit; wherein the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit; and wherein the third antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen-binding domain. In some aspects, the bispecific antibody is a 2+1 A / AB format (A: CCR8-binding domain), B: CD3-binding domain) anti- CCR8 / anti-CD3 bispecific antibody.

[0226] In some embodiments, the bispecific antibody described herein comprises a first Fab molecule (FabA) and a third Fab molecule (FabB2) that each specifically binds to CCR8 comprising Q39E (Kabat numbering) and S183K (EU numbering) substitutions in the heavy chain and Q38K (Kabat numbering) and V133E (EU numbering) substitutions in the light chain; and a second Fab molecule (Fabsi) that specifically binds to CD3 comprising Q39K (Kabat numbering) and S183E (EU numbering) substitution in the heavy chain and Q38E (Kabat numbering) and V133K (EU numbering) substitutions in the light chain.

[0227] In some aspects, the bispecific antibody comprises: a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAASGIDLSTYAMGWVREAPGKGLEWVGLIHRSGRTYYATWAKGRFTI SKDSSKNTLYLQMNSLRAEDTAVYYCTRSYPDYSATASIWGQGTTVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 17), a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of DIQVTQSPSSLPASVGDRVTITCQASENIANALAWYQKKPGKPPKFLIYGASNLASGVPSRFSGSGSGTD FTFTISSLQPEDIATYYCQQAYYGNSFVEGTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVECLLN NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC (SEQ ID NO: 18), a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAASGIDLSTYAMGWVREAPGKGLEWVGLIHRSGRTYYATWAKGRFTI SKDSSKNTLYLQMNSLRAEDTAVYYCTRSYPDYSATASIWGQGTTVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLKSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVRKAPGQGLEWIG WIYPGDGNTKYNEKFKGRATLTADTSTSTAYLELSSLRSEDTAVYYCARDSYSNYYFDYWGQGTLVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLESV VTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 19), and a polypeptide comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKSSQSLLNSRTRKNYLAWYQEKPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCTQSFILRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVKCLLN NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC (SEQ ID NO: 20).

[0228] In some embodiments, the bispecific antibody comprises a polypeptide comprising the amino acid sequence of SEQ ID NO: 17, a first polypeptide and a second polypeptide each comprising the amino acid sequence of SEQ ID NO: 18, a polypeptide comprising the amino acid sequence of SEQ ID NO: 19, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, (i) the polypeptide comprising the amino acid sequence of SEQ ID NO: 17 is connected to the first polypeptide comprising the amino acid sequence of SEQ ID NO: 18 via a Fab heavy chain and Fab light chain interaction; (ii) the polypeptide comprising the amino acid sequence of SEQ ID NO: 19 is connected to the second polypeptide comprising the amino acid sequence of SEQ ID NO: 18 via a Fab heavy chain and Fab light chain interaction; (iii) the polypeptide comprising the amino acid sequence of SEQ ID NO: 19 is connected to the polypeptide comprising the amino acid sequence of SEQ ID NO: 20 via a Fab heavy chain and Fab light chain interaction; and (iv) the polypeptide comprising the amino acid sequence of SEQ ID NO: 17 is connected to the polypeptide comprising the amino acid sequence of SEQ ID NO: 19 via a first subunit and a second subunit of an Fc domain. In some aspects, the bispecific antibody is a 2+1 A / AB format (A: 1189 P, B: 40G5c) 1189 / 1189:40G5c anti-CCR8 / anti-CD3 bispecific antibody.

[0229] In some aspects, the invention provides a bispecific antibody comprising: (a) a first antigenbinding domain that binds CCR8, wherein the first antigen-binding domain comprises the following six CDRs: (i) a CDR-H1 comprising the amino acid sequence TYAMG (SEQ ID NO: 1 ); (ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO: 2); (iii) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3); (iv) a CDR-L1 comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4); (v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and (vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6); (b) a second antigen-binding domain that binds CD3, wherein the second antigenbinding domain comprises the following six CDRs: (i) a CDR-H1 comprising the amino acid sequence NYYIH (SEQ ID NO: 7); (ii) a CDR-H2 comprising the amino acid sequence WIYPGDGNTKYNEKFKG (SEQ ID NO: 8); (iii) a CDR-H3 comprising the amino acid sequence DSYSNYYFDY (SEQ ID NO: 9); (iv) a CDR-L1 comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 10); (v) a CDR-L2 comprising the amino acid sequence WASTRES (SEQ ID NO: 11 ); and (vi) a CDR-L3 comprising the amino acid sequence TQSFILRT (SEQ ID NO: 12); and (c) a third antigen-binding domain that binds CCR8, wherein the third antigen-binding domain comprises the following six CDRs: (i) a CDR-H1 comprising the amino acid sequence TYAMG (SEQ ID NO: 1 ); (ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO: 2); (iii) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3); (iv) a CDR-L1 comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4); (v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and (vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6), wherein:

[0230] (A) (1 ) the first antigen-binding domain comprises a VL domain and a VH domain, wherein the VL domain comprises a proline residue at position 12 and a lysine residue at position 38, and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat); (2) the second antigenbinding domain comprises a VL domain and a VH domain, wherein the VL domain comprises a glutamic acid residue at position 38, and the VH domain comprises a lysine residue at position 39 (numbering according to Kabat); and (3) the third antigen-binding domain comprises a VL domain and a VH domain, wherein the VL domain comprises a proline residue at position 12 and a lysine residue at position 38, and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat);

[0231] (B) the first antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, the second antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, and the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, and wherein: (1 ) the Fab light chain of the first antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the first antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat); (2) the Fab light chain of the second antigen-binding domain comprises a lysine residue at position 133, and the Fab heavy chain of the second antigen-binding domain comprises a glutamic acid residue at position 183 (numbering according to Kabat); and (3) the Fab light chain of the third antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the third antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat); and

[0232] (C) the bispecific antigen-binding molecule further comprises an IgG Fc domain comprising a first subunit and a second subunit, wherein the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit, wherein the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit, wherein the third antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen-binding domain, and wherein: (1 ) each of the first subunit and the second subunit comprises an alanine residue at position 234, an alanine residue at position 235, and a glycine residue at position 329 (numbering according to Kabat EU index); and (2) the first subunit comprises a tryptophan residue at position 366; and the second subunit comprises a serine residue at position 366, an alanine residue at position 368, and a valine residue at position 407 (numbered according to Kabat EU index).

[0233] In some embodiments, the VH domain of first antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 7 and the VL domain of first antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 8; the VH domain of the second antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 23 and the VL domain of the second antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 24; and the VH domain of the third antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 7 and the VL domain of the third antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 8.

[0234] In some instances, the bispecific antibody described above was used in the Phase la / lb, Open- Label, Multicenter Study described in Example 2 below.

[0235] B. PD-L1 Binding Antagonists

[0236] In some instances, the methods described herein include administering an effective amount of the anti-CCR8 / anti-CD3 bispecific antibody in combination with an effective amount of PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) to a subject having a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HOC, among others). In some instances, the PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) inhibits the interaction between PD-L1 and its receptors (e.g., PD-1 and B7-1 (CD80)) that exert an inhibitory effect on effector T cells (e.g., CD8+ or CD4+ effector T cells), thus enhancing the magnitude and quality of the anti-tumor activity mediated by said effector cells.

[0237] In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 . In yet other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1 . In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1 . The PD-L1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 ). In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some instances, the PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some instances, the small molecule is a compound described in WO 2015 / 033301 and / or WO 2015 / 033299.

[0238] In some instances, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD- L1 antibodies are contemplated and described herein. In any of the instances herein, the isolated anti- PD-L1 antibody can bind to a human PD-L1 , for example, a human PD-L1 as shown in UniProtKB / Swiss- Prot Accession No. Q9NZQ7-1 , or a variant thereof. In some instances, the anti-PD-L1 antibody is capable of inhibiting binding between PD-L1 and PD-1 and / or between PD-L1 and B7-1 . In some instances, the anti-PD-L1 antibody is a monoclonal antibody. In some instances, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-L1 antibody is a humanized antibody. In some instances, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX- 1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. Examples of anti-PD-L1 antibodies useful in the methods of this invention and methods of making them are described in International Patent Application Publication No. WO 2010 / 077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

[0239] In some instances, the anti-PD-L1 antibody comprises:

[0240] (a) an HVR-H1 , HVR-H2, and HVR-H3 sequence of GFTFSDSWIH (SEQ ID NO: 41 ), AWISPYGGSTYYADSVKG (SEQ ID NO: 42) and RHWPGGFDY (SEQ ID NO: 43), respectively, and

[0241] (b) an HVR-L1 , HVR-L2, and HVR-L3 sequence of RASQDVSTAVA (SEQ ID NO: 44), SASFLYS (SEQ ID NO: 45) and QQYLYHPAT (SEQ ID NO: 46), respectively.

[0242] In one embodiment, the anti-PD-L1 antibody comprises:

[0243] (a) a heavy chain variable region (VH) comprising the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGR FTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 47), and

[0244] (b) a light chain variable region (VL) comprising the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 48).

[0245] In some instances, the anti-PD-L1 antibody comprises (a) a VH comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 47; (b) a VL comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 48; or (c) a VH as in (a) and a VL as in (b).

[0246] In one embodiment, the anti-PD-L1 antibody comprises atezolizumab, which comprises:

[0247] (a) the heavy chain amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGR FTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 49), and

[0248] (b) the light chain amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC (SEQ ID NO: 50).

[0249] In some instances, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal lgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

[0250] In some instances, the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60- 7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG 1 kappa anti-PD-L1 antibody (Medlmmune, AstraZeneca) described in WO 201 1 / 066389 and US 2013 / 034559.

[0251] In some instances, the anti-PD-L1 antibody is MDX-1 105 (Bristol Myers Squibb). MDX-1 105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007 / 005874.

[0252] In some instances, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

[0253] In some instances, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti- PD-L1 antibody.

[0254] In some instances, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is singledomain antibody (dAB) generated from a camel phage display library.

[0255] In some instances, the anti-PD-L1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates an antibody antigen binding domain to allow it to bind its antigen, e.g., by removing a non-binding steric moiety. In some instances, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

[0256] In some instances, the anti-PD-L1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and / or the heavy chain variable domain and light chain variable domain from an anti-PD-L1 antibody described in US 20160108123, WO 2016 / 000619, WO 2012 / 145493, U.S. Pat. No. 9,205,148, WO 2013 / 181634, or WO 2016 / 061 142.

[0257] In a still further specific aspect, the anti-PD-L1 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region. In still a further instance, the effector-less Fc mutation is an N297A substitution in the constant region. In some instances, the isolated anti-PD-L1 antibody is aglycosylated. Glycosylation of antibodies is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N- acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Removal of glycosylation sites from an antibody is conveniently accomplished by altering the amino acid sequence such that one of the abovedescribed tripeptide sequences (for N-linked glycosylation sites) is removed. The alteration may be made by substitution of an asparagine, serine or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution). C. Additional Therapeutic Agents

[0258] In some instances, the methods described herein include administering an effective amount of the anti-CCR8 / anti-CD3 bispecific antibody and / or an effective amount of a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) in combination with an effective amount of one or more additional therapeutic agents. In some instances, the one or more additional therapeutic agents may reduce the rate or the severity of cytokine release syndrome (CRS). In some instances, the one or more additional therapeutic agents may prevent symptoms associated with CRS. In particular instances, the additional therapeutic agent used to reduce the rate or severity of CRS or prevent symptoms associated with CRS is a corticosteroid (e.g., dexamethasone (CAS#: 50-02-2), prednisone (CAS#: 53-03-2), prednisolone (CAS# 50-42-8), or methylprednisolone (CAS#: 83-43-2)) or an IL-6R antagonist (e.g., tocilizumab (CAS#: 375823-41 -9), sarilumab (CAS#: 1189541 -98-7), vobarilizumab (ALX-0061 ; CAS#: 1628814-88-9), satralizumab (SA-237; CAS#: 1535963-91 -7), and variants thereof).

[0259] In some instances, the additional therapeutic agent is tocilizumab. In some instances, the additional therapeutic agent is a corticosteroid. In some instances, the corticosteroid is dexamethasone. In some instances, the corticosteroid is prednisone. In some instances, the corticosteroid is methylprednisolone.

[0260] In some instances, the one or more additional therapeutic agents is acetaminophen or paracetamol. Acetaminophen or paracetamol has the CAS#: 103-90-2.

[0261] In some instances, the one or more additional therapeutic agents is an antihistamine. In some instances, the one or more additional therapeutic agents is diphenhydramine. Diphenhydramine has the CAS#: 58-73-1 .

[0262] V. Pharmaceutical Compositions

[0263] In some embodiments, the anti-CCR8 / anti-CD3 bispecific antibody is provided in the following configuration:

[0264] The drug product formulation is supplied in single-dose 6 mL glass vials containing 3.0 mL of the anti-CCR8 / anti-CD3 bispecific antibody liquid drug product buffered in L-histidine acetate solution containing polysorbate 20, sucrose, L-methionine, and water for injection (WFI). The approximate concentration of the anti-CCR8 / anti-CD3 bispecific antibody in the vials is 100 mg / mL.

[0265] Diluent is provided in single-dose 50mL glass vials containing 35.0 mL of L-histidine acetate solution containing polysorbate 20, sucrose, and WFI.

[0266] VI. Kits and Articles of Manufacture

[0267] In another aspect of the invention, a kit or an article of manufacture containing materials (e.g., the anti-CCR8 / anti-CD3 bispecific antibody alone, or in combination with the PD-L1 binding antagonist (e.g., the anti-PD-L1 antibody; e.g., atezolizumab), or pharmaceutical compositions thereof) useful for the treatment, prevention, and / or diagnosis of the disorders (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others) described above is provided. The kit or article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and / or diagnosing 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). At least one active agent in the composition is an anti-CCR8 / anti-CD3 bispecific antibody and / or a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab). The label or package insert indicates that the composition is used for treating the condition of choice (e.g., a cell proliferative disorder (e.g., a cancer; e.g., a solid tumor malignancy, such as NSCLC, HNSCC, cutaneous melanoma, TNBC, UCC, esophageal cancer, gastric cancer, GEJ adenocarcinoma, ccRCC, and HCC, among others)) and further includes information related to at least one of the dosing regimens described herein. The kit or article of manufacture may comprise a container with a composition contained therein, wherein the composition comprises an anti-CCR8 / anti-CD3 bispecific antibody described herein and / or a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) described herein. Alternatively, the kit or article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an anti-CCR8 / anti-CD3 bispecific antibody described herein, a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody; e.g., atezolizumab) described herein, or both an anti-CCR8 / anti- CD3 bispecific antibody and a PD-L1 binding antagonist; and / or (b) a second container with a composition contained therein, wherein the composition comprises an additional therapeutic agent (e.g., a further cytotoxic or otherwise therapeutic agent). Alternatively, or additionally, the kit or article of manufacture may further comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), 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, and syringes.

[0268] VII. Embodiments

[0269] 1 . A method of treating a subject having a cell proliferative disorder, the method comprising administering to the subject an effective amount of a bispecific antibody that binds C-C motif chemokine receptor 8 (CCR8) and cluster of differentiation 3 (CD3) in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg.

[0270] 2. A bispecific antibody that binds CCR8 and CD3 for use in treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg.

[0271] 3. Use of a bispecific antibody that binds CCR8 and CD3 for treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg.

[0272] 4. Use of a bispecific antibody that binds CCR8 and CD3 in the manufacture of a medicament for treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg.

[0273] 5. The method, bispecific antibody for use, or use of any one of embodiments 1 -4, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg.

[0274] 6. The method, bispecific antibody for use, or use of embodiment 5, wherein the Cycle 1 , Dose 1 of the bispecific antibody is

[0275] (a) from about 0.9 mg to about 100 mg; or

[0276] (b) from about 1 .8 mg to about 300 mg.

[0277] 7. The method, bispecific antibody for use, or use of embodiment 5, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg.

[0278] 8. The method, bispecific antibody for use, or use of any one of embodiments 1 -4, wherein the Cycle 1 , Dose 1 of the bispecific antibody is about 0.1 mg, about 0.45 mg, or about 0.9 mg.

[0279] 9. The method, bispecific antibody for use, or use of any one of embodiments 1 -4, wherein the Cycle 1 , Dose 1 of the bispecific antibody is about 1 .8 mg, about 100 mg, or about 300 mg.

[0280] 10. The method, bispecific antibody for use, or use of any one of embodiments 1 -9, wherein the length of the first dosing cycle is about 21 days.

[0281] 11 . The method, bispecific antibody for use, or use of embodiment 10, wherein the Cycle 1 , Dose 1 of the bispecific antibody is administered or is to be administered to the subject on about Day 1 of the first dosing cycle.

[0282] 12. The method, bispecific antibody for use, or use of any one of embodiments 1 -11 , wherein the dosing regimen comprises one or more additional dosing cycles.

[0283] 13. The method, bispecific antibody for use, or use of embodiment 12, wherein the dosing regimen comprises one to six additional dosing cycles.

[0284] 14. The method, bispecific antibody for use, or use of embodiment 12 or 13, wherein the length of each of the one or more additional dosing cycles is about 21 days.

[0285] 15. The method, bispecific antibody for use, or use of any one of embodiments 12-14, wherein each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody.

[0286] 16. The method, bispecific antibody for use, or use of embodiment 15, wherein each single dose of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 1 of the bispecific antibody.

[0287] 17. The method, bispecific antibody for use, or use of embodiment 15 or 16, wherein each single dose of the bispecific antibody is administered or is to be administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0288] 18. A method of treating a subject having a cell proliferative disorder, the method comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher in amount than the Cycle 1 , Dose 1 of the bispecific antibody; and

[0289] (b) the second dosing cycle comprises a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody.

[0290] 19. A bispecific antibody that binds CCR8 and CD3 for use in treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

[0291] (a) the first dosing cycle comprises a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher in amount than the Cycle 1 , Dose 1 of the bispecific antibody; and

[0292] (b) the second dosing cycle comprises a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody.

[0293] 20. Use of a bispecific antibody that binds CCR8 and CD3 in treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

[0294] (a) the first dosing cycle comprises a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher in amount than the Cycle 1 , Dose 1 of the bispecific antibody; and

[0295] (b) the second dosing cycle comprises a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody.

[0296] 21 . Use of bispecific antibody that binds CCR8 and CD3 in the manufacture of a medicament for treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

[0297] (a) the first dosing cycle comprises a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher in amount than the Cycle 1 , Dose 1 of the bispecific antibody; and

[0298] (b) the second dosing cycle comprises a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody.

[0299] 22. The method, bispecific antibody that binds CCR8 and CD3 for use, or use of any one of embodiments 14-17, wherein the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg or about 1 .8 mg and the Cycle 1 , Dose 2 of the bispecific antibody is about 3 mg.

[0300] 23. The method, bispecific antibody that binds CCR8 and CD3 for use, or use of any one of embodiments 14-22, wherein: (a) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg;

[0301] (b) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg;

[0302] (c) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg;

[0303] (d) the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg;

[0304] (e) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg; or

[0305] (f) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg.

[0306] 24. The method, bispecific antibody for use, or use of any one of embodiments 18-23, wherein the length of the first dosing cycle is about 21 days.

[0307] 25. The method, bispecific antibody for use, or use of embodiment 24, wherein the Cycle 1 , Dose 1 and the Cycle 1 , Dose 2 of the bispecific antibody are administered or are to be administered to the subject on about Day 1 and about Day 8, respectively, of the first dosing cycle.

[0308] 26. The method, bispecific antibody for use, or use of any one of embodiments 18-25, wherein the length of the second dosing cycle is about 21 days.

[0309] 27. The method, bispecific antibody for use, or use of embodiment 26, wherein the Cycle 2, Dose 1 of the bispecific antibody is administered or is to be administered to the subject on about Day 1 of the second dosing cycle.

[0310] 28. The method, bispecific antibody for use, or use of any one of embodiments 18-27, wherein the dosing regimen comprises one or more additional dosing cycles.

[0311] 29. The method, bispecific antibody for use, or use of embodiment 28, wherein the dosing regimen comprises one to six additional dosing cycles.

[0312] 30. The method, bispecific antibody for use, or use of embodiment 28 or 29, wherein the length of each of the one or more additional dosing cycles is about 21 days.

[0313] 31 . The method, bispecific antibody for use, or use of any one of embodiments 28-30, wherein each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody.

[0314] 32. The method, bispecific antibody for use, or use of embodiment 31 , wherein each single dose of the bispecific antibody is about equivalent in amount to the Cycle 2, Dose 1 of the bispecific antibody.

[0315] 33. The method, bispecific antibody for use, or use of embodiment 31 or 32, wherein each single dose of the bispecific antibody is administered or is to be administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0316] 34. A method of treating a subject having a cell proliferative disorder, the method comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 and an effective amount of atezolizumab in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises:

[0317] (a) a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody; and (b) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg.

[0318] 35. A bispecific antibody that binds CCR8 and CD3 and atezolizumab for use in treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises:

[0319] (a) a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody; and

[0320] (b) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg.

[0321] 36. Use of a bispecific antibody that binds CCR8 and CD3 and atezolizumab in treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises:

[0322] (a) a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody; and

[0323] (b) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg.

[0324] 37. Use of a bispecific antibody that binds CCR8 and CD3 in the manufacture of a medicament for use in combination with atezolizumab for treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises:

[0325] (a) a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody; and

[0326] (b) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg.

[0327] 38. Use of atezolizumab in the manufacture of a medicament for use in combination with a bispecific antibody that binds CCR8 and CD3 for treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises:

[0328] (a) a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody; and

[0329] (b) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg.

[0330] 39. Use of a bispecific antibody that binds CCR8 and CD3 and atezolizumab in the manufacture of a medicament for treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises:

[0331] (a) a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody; and

[0332] (b) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg. 40. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 34- 39, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg, from about 1 .8 mg to about 300 mg, from about 0.9 mg to about 100 mg, from about 1 .8 mg to about 100 mg, or from about 100 mg to about 300 mg.

[0333] 41 . The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 34-39, wherein the Cycle, Dose 1 of the bispecific antibody is about 0.9 mg, about 1 .8 mg, about 100 mg, or about 300 mg.

[0334] 42. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 34- 41 , wherein the length of the first dosing cycle is about 21 days.

[0335] 43. The method, bispecific antibody and atezolizumab for use, or use of embodiment 42, wherein the Cycle 1 , Dose 1 of the bispecific antibody is administered or is to be administered to the subject on about Day 1 of the first dosing cycle.

[0336] 44. The method, bispecific antibody and atezolizumab for use, or use of embodiment 42 or 43, wherein the Cycle 1 , Dose 1 of atezolizumab is administered or is to be administered to the subject on about Day 1 of the first dosing cycle.

[0337] 45. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 34-

[0338] 44, wherein the Cycle 1 , Dose 1 of the bispecific antibody and the Cycle 1 , Dose 1 of atezolizumab are administered or are to be administered to the subject on about the same day in the first dosing cycle.

[0339] 46. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 34-

[0340] 45, wherein the dosing regimen comprises one or more additional dosing cycles.

[0341] 47. The method, bispecific antibody and atezolizumab for use, or use of embodiment 46, wherein the dosing regimen comprises one to six additional dosing cycles.

[0342] 48. The method, bispecific antibody and atezolizumab for use, or use of embodiment 46 or 47, wherein the length of each of the one or more additional dosing cycles is about 21 days.

[0343] 49. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 46- 48, wherein each of the one or more additional dosing cycles comprises:

[0344] (a) a single dose of the bispecific antibody; and

[0345] (b) a single dose of atezolizumab, wherein the single dose of atezolizumab is about 1200 mg.

[0346] 50. The method, bispecific antibody and atezolizumab for use, or use of embodiment 49, wherein each single dose of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 1 of the bispecific antibody.

[0347] 51 . The method, bispecific antibody and atezolizumab for use, or use of embodiment 49 or 50, wherein the single dose of the bispecific antibody is administered or is to be administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0348] 52. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 49-

[0349] 51 , wherein the single dose of atezolizumab is administered or is to be administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0350] 53. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 49-

[0351] 52, wherein the single dose of the bispecific antibody and the single dose of atezolizumab are administered or are to be administered to the subject on about the same day in each of the one or more additional dosing cycles.

[0352] 54. A method of treating a subject having a cell proliferative disorder, the method comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 and an effective amount of atezolizumab in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

[0353] (a) the first dosing cycle comprises:

[0354] (i) a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher than the Cycle 1 , Dose 1 of the bispecific antibody; and

[0355] (ii) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg; and

[0356] (b) the second dosing cycle comprises:

[0357] (i) a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody; and

[0358] (ii) a single dose (Cycle 2, Dose 1 ) of atezolizumab, wherein the Cycle 2, Dose 1 of atezolizumab is about 1200 mg.

[0359] 55. A bispecific antibody that binds CCR8 and CD3 and atezolizumab for use in treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

[0360] (a) the first dosing cycle comprises:

[0361] (i) a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher than the Cycle 1 , Dose 1 of the bispecific antibody; and

[0362] (ii) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg; and

[0363] (b) the second dosing cycle comprises:

[0364] (i) a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody; and

[0365] (ii) a single dose (Cycle 2, Dose 1 ) of atezolizumab, wherein the Cycle 2, Dose 1 of atezolizumab is about 1200 mg.

[0366] 56. Use of bispecific antibody that binds CCR8 and CD3 and atezolizumab for in treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

[0367] (a) the first dosing cycle comprises:

[0368] (i) a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher than the Cycle 1 , Dose 1 of the bispecific antibody; and (ii) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg; and

[0369] (b) the second dosing cycle comprises:

[0370] (i) a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody; and

[0371] (ii) a single dose (Cycle 2, Dose 1 ) of atezolizumab, wherein the Cycle 2, Dose 1 of atezolizumab is about 1200 mg.

[0372] 57. Use of a bispecific antibody that binds CCR8 and CD3 in the manufacture of a medicament for use in combination with atezolizumab for treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

[0373] (a) the first dosing cycle comprises:

[0374] (i) a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher than the Cycle 1 , Dose 1 of the bispecific antibody; and

[0375] (ii) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg; and

[0376] (b) the second dosing cycle comprises:

[0377] (i) a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody; and

[0378] (ii) a single dose (Cycle 2, Dose 1 ) of atezolizumab, wherein the Cycle 2, Dose 1 of atezolizumab is about 1200 mg.

[0379] 58. Use of atezolizumab in the manufacture of a medicament for use in combination with a bispecific antibody that binds CCR8 and CD3 for treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

[0380] (a) the first dosing cycle comprises:

[0381] (i) a first dose (Cycle 1 , Dose 1 ) and a second dose () of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher than the Cycle 1 , Dose 1 of the bispecific antibody; and

[0382] (ii) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg; and

[0383] (b) the second dosing cycle comprises:

[0384] (i) a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody; and

[0385] (ii) a single dose (Cycle 2, Dose 1 ) of atezolizumab, wherein the Cycle 2, Dose 1 of atezolizumab is about 1200 mg. 59. Use of bispecific antibody that binds CCR8 and CD3 and atezolizumab in the manufacture of a medicament for treating a subject having a cell proliferative disorder, wherein an effective amount of the bispecific antibody and an effective amount of atezolizumab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

[0386] (a) the first dosing cycle comprises:

[0387] (i) a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher than the Cycle 1 , Dose 1 of the bispecific antibody; and

[0388] (ii) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg; and

[0389] (b) the second dosing cycle comprises:

[0390] (i) a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody; and

[0391] (ii) a single dose (Cycle 2, Dose 1 ) of atezolizumab, wherein the Cycle 2, Dose 1 of atezolizumab is about 1200 mg.

[0392] 60. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 54- 59, wherein the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg or about 1 .8 mg and the Cycle 1 , Dose 2 of the bispecific antibody is about 3 mg.

[0393] 61 . The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 54-59, wherein:

[0394] (a) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg;

[0395] (b) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg;

[0396] (c) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg;

[0397] (d) the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg;

[0398] (e) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg; or

[0399] (f) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg.

[0400] 62. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 54- 61 , wherein the length of the first dosing cycle is about 21 days.

[0401] 63. The method, bispecific antibody and atezolizumab for use, or use of embodiment 62, wherein the Cycle 1 , Dose 1 and the Cycle 1 , Dose 2 of the bispecific antibody are administered or are to be administered to the subject on about Day 1 and about Day 8, respectively, of the first dosing cycle.

[0402] 64. The method, bispecific antibody and atezolizumab for use, or use of embodiment 62 or 63, wherein the Cycle 1 , Dose 1 of atezolizumab is administered or is to be administered to the subject on about Day 1 of the first dosing cycle. 65. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 54-

[0403] 64, wherein the Cycle 1 , Dose 1 of the bispecific antibody and the Cycle 1 , Dose 1 of atezolizumab are administered or are to be administered to the subject on about the same day in the first dosing cycle.

[0404] 66. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 54-

[0405] 65, wherein the length of the second dosing cycle is about 21 days.

[0406] 67. The method, bispecific antibody and atezolizumab for use, or use of embodiment 66, wherein the Cycle 2, Dose 1 of the bispecific antibody is administered or is to be administered to the subject on about Day 1 of the second dosing cycle.

[0407] 68. The method, bispecific antibody and atezolizumab for use, or use of embodiment 66 or 67, wherein the Cycle 2, Dose 1 of atezolizumab is administered or is to be administered to the subject on about Day 1 of the second dosing cycle.

[0408] 69. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 54-

[0409] 68, wherein the Cycle 2, Dose 1 of the bispecific antibody and the Cycle 2, Dose 1 of atezolizumab are administered or are to be administered to the subject on about the same day in the second dosing cycle.

[0410] 70. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 54-

[0411] 69, wherein the dosing regimen comprises one or more additional dosing cycles.

[0412] 71 . The method, bispecific antibody and atezolizumab for use, or use of embodiment 70, wherein the dosing regimen comprises one to six additional dosing cycles.

[0413] 72. The method, bispecific antibody and atezolizumab for use, or use of embodiment 70 or 71 , wherein the length of each of the one or more additional dosing cycles is about 21 days.

[0414] 73. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 70- 72, wherein each of the one or more additional dosing cycles comprises:

[0415] (a) a single dose of the bispecific antibody; and

[0416] (b) a single dose of atezolizumab, wherein the single dose of atezolizumab is about 1200 mg.

[0417] 74. The method, bispecific antibody and atezolizumab for use, or use of embodiment 73, wherein each single dose of the bispecific antibody is about equivalent in amount to the Cycle 2, Dose 1 of the bispecific antibody.

[0418] 75. The method, bispecific antibody and atezolizumab for use, or use of embodiment 73 or 74, wherein the single dose of the bispecific antibody is administered or is to be administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0419] 76. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 72-

[0420] 75, wherein the single dose of atezolizumab is administered or is to be administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

[0421] 77. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 72-

[0422] 76, wherein the single dose of the bispecific antibody and the single dose of atezolizumab are administered or are to be administered to the subject on about the same day in each of the one or more additional dosing cycles.

[0423] 78. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 34-

[0424] 77, wherein atezolizumab is administered or is to be administered intravenously. 79. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 34-

[0425] 78, wherein when the bispecific antibody and atezolizumab are administered or are to be administered on about the same day, the bispecific antibody is administered or is to be administered at least 30 minutes after the end of the administration of atezolizumab.

[0426] 80. The method, bispecific antibody and atezolizumab for use, or use of any one of embodiments 34-

[0427] 79, wherein when the bispecific antibody and atezolizumab are administered or are to be administered on about the same day, the bispecific antibody is administered or is to be administered at least 60 minutes after the end of the administration of atezolizumab.

[0428] 81 . The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -80, wherein the bispecific antibody is administered or is to be administered intravenously.

[0429] 82. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -78, 80, and 81 , wherein the method or use further comprises administering to the subject an effective amount of a corticosteroid.

[0430] 83. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 82, wherein the corticosteroid is dexamethasone or methylprednisolone.

[0431] 84. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 83, wherein:

[0432] (a) the corticosteroid is dexamethasone, and wherein dexamethasone is administered or is to be administered at a dose of about 20 mg; or

[0433] (b) the corticosteroid is methylprednisolone, and wherein methylprednisolone is administered or is to be administered at a dose of about 80 mg.

[0434] 85. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 82-84, wherein the corticosteroid is administered or is to be administered about one hour prior to the start of the administration of any dose of the bispecific antibody in the first dosing cycle.

[0435] 86. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 82-85, wherein when the bispecific antibody, atezolizumab, and the corticosteroid are administered or are to be administered on about the same day, the corticosteroid is administered or is to be administered at least 60 minutes after the end of the administration of atezolizumab and about one hour prior to the start of the administration of the bispecific antibody.

[0436] 87. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 82-86, wherein the subject experiences cytokine release syndrome (CRS), infusion-related reaction (IRR), or immune effector cell-associated neurotoxicity syndrome (ICANS) in a dosing cycle, and wherein the corticosteroid is administered or is to be administered about one hour prior to the start of the administration of the bispecific antibody in the next dosing cycle.

[0437] 88. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 82-80, wherein the method or use further comprises administering to the subject an effective amount of tocilizumab. 89. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 88, wherein tocilizumab is administered or is to be administered at a dose of about 8 mg / kg or about 12 mg / kg.

[0438] 90. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -89, wherein the subject experiences CRS after being administered the bispecific antibody, and wherein:

[0439] (a) dexamethasone is administered or is to be administered to the subject about every 6 hours; or

[0440] (b) tocilizumab and dexamethasone are administered or are to be administered to the subject about every 6 hours.

[0441] 91 . The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 90, wherein dexamethasone is administered or is to be administered at a dose of about 10 mg; and / or wherein tocilizumab is administered or is to be administered at a dose of about 8 mg / kg or about 12 mg / kg.

[0442] 92. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 99-91 , wherein tocilizumab is administered or is to be administered intravenously.

[0443] 93. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 82-92, wherein the corticosteroid is administered or is to be administered intravenously.

[0444] 94. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -93, wherein the method or use further comprises administering to the subject an effective amount of an antihistamine.

[0445] 95. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 94, wherein the antihistamine is diphenhydramine.

[0446] 96. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 95, wherein diphenhydramine is administered or is to be administered at a dose of from about 25 mg to about 50 mg.

[0447] 97. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 94-96, wherein the antihistamine is administered or is to be administered at least about 30 minutes prior to the start of the administration of any dose of the bispecific antibody.

[0448] 98. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 94-97, wherein the antihistamine is administered or is to be administered orally.

[0449] 99. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -98, wherein the method or use further comprises administering to the subject an effective amount of acetaminophen (paracetamol).

[0450] 100. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 99, wherein acetaminophen (paracetamol) is administered or is to be administered at a dose of from about 500 mg to about 1 ,000 mg. 101 . The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 99 or 100, wherein acetaminophen (paracetamol) is administered or is to be administered at least about 30 minutes prior to the start of the administration of any dose of the bispecific antibody.

[0451] 102. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 99-101 , wherein acetaminophen (paracetamol) is administered or is to be administered orally.

[0452] 103. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -102, wherein the bispecific antibody comprises:

[0453] (a) a first antigen-binding domain that binds CCR8, wherein the first antigen-binding domain comprises the following six complementarity-determining regions (CDRs):

[0454] (i) a heavy chain CDR 1 (CDR-H1 ) comprising the amino acid sequence TYAMG (SEQ ID NO: 1 );

[0455] (ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO: 2);

[0456] (Hi) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3);

[0457] (iv) a light chain CDR 1 (CDR-L1 ) comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4);

[0458] (v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and

[0459] (vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6);

[0460] (b) a second antigen-binding domain that binds CD3, wherein the second antigen-binding domain comprises the following six CDRs:

[0461] (i) a CDR-H1 comprising the amino acid sequence NYYIH (SEQ ID NO: 7);

[0462] (ii) a CDR-H2 comprising the amino acid sequence WIYPGDGNTKYNEKFKG (SEQ ID NO:

[0463] 8);

[0464] (Hi) a CDR-H3 comprising the amino acid sequence DSYSNYYFDY (SEQ ID NO: 9);

[0465] (iv) a CDR-L1 comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO:

[0466] 10);

[0467] (v) a CDR-L2 comprising the amino acid sequence WASTRES (SEQ ID NO: 11 ); and

[0468] (vi) a CDR-L3 comprising the amino acid sequence TQSFILRT (SEQ ID NO: 12); and

[0469] (c) a third antigen-binding domain that binds CCR8, wherein the third antigen-binding domain comprises the following six CDRs:

[0470] (i) a CDR-H1 comprising the amino acid sequence TYAMG (SEQ ID NO: 1 );

[0471] (ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO:

[0472] 2);

[0473] (Hi) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3);

[0474] (iv) a CDR-L1 comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4);

[0475] (v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and

[0476] (vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6). 104. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 103, wherein the first antigen-binding domain comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, and wherein:

[0477] (a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); and / or

[0478] (b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat).

[0479] 105. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 103 or 104, wherein the second antigen-binding domain comprises a VL domain and a VH domain, and wherein the VL domain comprises a glutamic acid residue at position 38 and the VH domain comprises a lysine residue at position 39 (numbering according to Kabat).

[0480] 106. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 103-105, wherein the third antigen-binding domain comprises a VL domain and a VH domain, and wherein:

[0481] (a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); and / or

[0482] (b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat).

[0483] 107. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 103-106, wherein:

[0484] (a) the first antigen-binding domain comprises:

[0485] (i) a VH domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 13;

[0486] (ii) a VL domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 14; or

[0487] (Hi) a VH domain as in (i) and a VL domain as in (ii);

[0488] (b) the second antigen-binding domain comprises:

[0489] (i) a VH domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 15;

[0490] (ii) a VL domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 16; or

[0491] (Hi) a VH domain as in (i) and a VL domain as in (ii); and / or

[0492] (c) the third antigen-binding domain comprises:

[0493] (i) a VH domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 13;

[0494] (ii) a VL domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 14; or

[0495] (Hi) a VH domain as in (i) and a VL domain as in (ii).

[0496] 108. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiments 107, wherein:

[0497] (a) the first antigen-binding domain comprises:

[0498] (i) a VH domain comprising the amino acid sequence of SEQ ID NO: 13; (ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 14; or

[0499] (iii) a VH domain as in (i) and a VL domain as in (ii);

[0500] (b) the second antigen-binding domain comprises:

[0501] (i) a VH domain comprising the amino acid sequence of SEQ ID NO: 15;

[0502] (ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 16; or

[0503] (iii) a VH domain as in (i) and a VL domain as in (ii); and / or

[0504] (c) the third antigen-binding domain comprises:

[0505] (i) a VH domain comprising the amino acid sequence of SEQ ID NO: 13;

[0506] (ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 14; or

[0507] (iii) a VH domain as in (i) and a VL domain as in (ii).

[0508] 109. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 103-108, wherein each of the first, the second, and / or the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain.

[0509] 110. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 109, wherein each of the first, the second, and the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, and wherein:

[0510] (a) the Fab light chain of the first antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the first antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat);

[0511] (b) the Fab light chain of the second antigen-binding domain comprises a lysine residue at position 133, and the Fab heavy chain of the second antigen-binding domain comprises a glutamic acid residue at position 183 (numbering according to Kabat); and / or

[0512] (c) the Fab light chain of the third antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the third antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat).

[0513] 111. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 103-110, wherein the second antigen-binding domain and the third antigenbinding domain are fused to each other.

[0514] 112. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 111 , wherein the second antigen-binding domain and the third antigen-binding domain are fused to each other via a peptide linker.

[0515] 113. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 112, wherein the peptide linker comprises the amino acid sequence of SEQ ID NO: 21 .

[0516] 114. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 111 -113, wherein each of the second antigen-binding domain and the third antigen-binding domain is a Fab molecule, and wherein the third antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigenbinding domain. 115. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 103-114, wherein the bispecific antibody further comprises an Fc domain comprising a first subunit and a second subunit.

[0517] 116. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 115, wherein the Fc domain is an IgG Fc domain.

[0518] 117. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 116, wherein the Fc domain is an IgG 1 Fc domain.

[0519] 118. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 115-117, wherein the Fc domain is a human IgG Fc domain.

[0520] 119. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 115-118, wherein the Fc domain comprises a modification promoting the association of the first subunit and the second subunit of the Fc domain.

[0521] 120. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 115-119, wherein each of the first and the second subunit comprises an alanine residue at position 234, an alanine residue at position 235, and a glycine residue at position 329 (numbering according to Kabat EU index).

[0522] 121 . The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 103-120, wherein the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH2i) domain, a first CH3 (CH3i) domain, a second CH1 (CHI2) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain.

[0523] 122. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 115-120, wherein the first subunit comprises one or more heavy chain constant domains selected from a first CH2 (CH2i) domain and / or a first CH3 (CH3i) domain; and the second subunit comprises one or more heavy chain constant domains selected from a second CH2 (CH22) domain and / or a second CH3 (CH32) domain.

[0524] 123. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 122, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

[0525] 124. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 123, wherein each of the CH3i and CH32 domains comprises a protuberance or cavity, and wherein the protuberance or cavity in the CH3i domain is positionable in the cavity or protuberance, respectively, in the CH32 domain.

[0526] 125. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 124, wherein the CH3i and CH32 domains meet at an interface between said protuberance and cavity.

[0527] 126. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 122-125, wherein the CH2i and CH22 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2i domain is positionable in the cavity or protuberance, respectively, in the CH22 domain. 127. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 126, wherein the CH2i and CH22 domains meet at an interface between said protuberance and cavity.

[0528] 128. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 125-127, wherein:

[0529] (a) the first subunit comprises a tryptophan residue at position 366 (numbered according to Kabat EU index); and

[0530] (b) the second subunit comprises a serine residue at position 366, an alanine residue at position 368, and a valine residue at position 407 (numbered according to Kabat EU index).

[0531] 129. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 109-128, wherein each of the first antigen-binding domain and the second antigen-binding domain is a Fab molecule, wherein the bispecific antibody comprises an Fc domain comprising a first subunit and a second subunit, and wherein:

[0532] (a) the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the first subunit; and

[0533] (b) the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the second subunit.

[0534] 130. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 109-129, wherein each of the first, the second, and the third antigen-binding domain is a Fab molecule, wherein the bispecific antibody comprises an Fc domain comprising a first subunit and a second subunit, and wherein:

[0535] (a) the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the first subunit;

[0536] (b) the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the second subunit; and

[0537] (c) the third antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the Fab heavy chain of the second antigen-binding domain.

[0538] 131 . The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 103-130, wherein the bispecific antibody comprises:

[0539] (a) a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 17;

[0540] (b) a first polypeptide and a second polypeptide each comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 18;

[0541] (c) a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 19; and

[0542] (d) a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 20.

[0543] 132. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 131 , wherein the bispecific antibody comprises:

[0544] (a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 17; (b) a first polypeptide and a second polypeptide each comprising the amino acid sequence of SEQ ID NO: 18;

[0545] (c) a polypeptide comprising the amino acid sequence of SEQ ID NO: 19; and

[0546] (d) a polypeptide comprising the amino acid sequence of SEQ ID NO: 20.

[0547] 133. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -132, wherein the subject is a human.

[0548] 134. The method of any one of embodiments 1 -133, wherein:

[0549] (a) the subject has progressed after at least one available standard therapy; and / or

[0550] (b) the subject is one for whom all available standard therapy has been proven to be ineffective or intolerable or is contraindicated.

[0551] 135. The method of any one of embodiments 1 -134, wherein the subject’s age is 18 years or older.

[0552] 136. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -135, wherein the cell proliferation disorder is a cancer.

[0553] 137. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -136, wherein the cell proliferation disorder is a solid tumor malignancy.

[0554] 138. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -137, wherein the cell proliferation disorder is a locally advanced, recurrent, or metastatic incurable solid tumor malignancy.

[0555] 139. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -138, wherein the cell proliferation disorder is selected from the group consisting of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), cutaneous melanoma, triple-negative breast cancer (TNBC), urothelial carcinoma (UCC), esophageal cancer, gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, clear cell renal cell carcinoma (ccRCC), and hepatocellular carcinoma (HOC).

[0556] 140. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -139, wherein the subject is checkpoint inhibitor (CPI)-naTve.

[0557] 141 . The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 140, wherein the cell proliferation disorder is NSCLC, and wherein the subject has a tumor cell (TC) PD-L1 expression of > 50%, or an immune cell (IC) PD-L1 expression of > 10%.

[0558] 142. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 140, wherein the cell proliferation disorder is HNSCC, and wherein the subject has a combined TC / IC PD-L1 expression of > 20.

[0559] 143. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 140, wherein the cell proliferation disorder is HNSCC, and wherein the subject has a combined TC / IC PD-L1 expression of > 1 and < 19.

[0560] 144. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 142 or 143, wherein the combined TC / IC PD-L1 expression is determined as tumor area positivity (TAP) or combined positive score (CPS). 145. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 140, wherein the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 20%.

[0561] 146. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 140, wherein the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 5% to > 19%.

[0562] 147. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -139, wherein the subject is CPI-experienced.

[0563] 148. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 140, wherein the cell proliferation disorder is NSCLC, HNSCC, gastric cancer, GEJ adenocarcinoma, HCC, ccRCC, TNBC, or UCC, and wherein the subject has a TC, IC, or combined TC / IC PD-L1 expression of > 1 or 1%.

[0564] 149. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 147, wherein the cell proliferation disorder is esophageal cancer, and wherein the subject has a TC, IC, or combined TC / IC PD-L1 expression of > 10 or 10%.

[0565] 150. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 148 or 149, wherein the combined TC / IC PD-L1 expression is determined as CPS, TAP, or tumor proportion score (TPS).

[0566] 151 . The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 147, wherein the cell proliferation disorder is NSCLC, and wherein the subject has an IC PD- L1 expression of > 1%.

[0567] 152. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 147, wherein the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 5%.

[0568] 153. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 147, wherein the cell proliferation disorder is gastric cancer or GEJ adenocarcinoma, and wherein the subject has a PD-L1 TAP of > 1%.

[0569] 154. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 147, wherein the cell proliferation disorder is ccRCC, TNBC, or UCC, and wherein the subject has an IC PD-L1 expression of > 1%.

[0570] 155. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 147, wherein the cell proliferation disorder is esophageal cancer, and wherein the subject has a PD-L1 TAP of > 10%.

[0571] 156. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 139, wherein the cell proliferative disorder is NSCLC or HNSCC.

[0572] 157. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 156, wherein the HNSCC is HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx.

[0573] 158. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 136-157, wherein the subject’s tumor comprises a targetable somatic alteration, and the subject has experienced disease progression during or after treatment, or intolerance to treatment, with a targeted agent.

[0574] 159. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 158, wherein the targetable somatic alteration comprises a somatic alteration involving epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1 ), proto-oncogene B-Raf (BRAF) V600E, neurotrophic tyrosine receptor kinase (NTRK), MET proto-oncogene (MET), RET proto-oncogene (RET), or Kirsten rat sarcoma virus (KRAS).

[0575] 160. The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of embodiment 139, wherein the cell proliferation disorder is cutaneous melanoma, wherein the subject’s tumor comprises a BRAFV600 mutation, and wherein the subject has experienced disease progression during or after treatment, or intolerance to treatment, with one or more serine / threonine-protein kinase B- Raf (BRAF) inhibitors and / or one or more mitogen-activated protein kinase kinase (MEK) inhibitors.

[0576] 161 . The method, bispecific antibody for use, bispecific antibody and atezolizumab for use, or use of any one of embodiments 1 -160, wherein the method or use further comprises determining the expression level of programmed death-ligand 1 (PD-L1 ) in a sample obtained from the subject.

[0577] 162. The...

Claims

CLAIMS1 . A method of treating a subject having a cell proliferative disorder, the method comprising administering to the subject an effective amount of a bispecific antibody that binds C-C motif chemokine receptor 8 (CCR8) and cluster of differentiation 3 (CD3) in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.1 mg to about 300 mg.

2. The method of claim 1 , wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg.

3. The method of claim 2, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg.

4. The method of claim 2, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg.

5. The method of claim 1 , wherein the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg.

6. The method of claim 1 , wherein the Cycle 1 , Dose 1 of the bispecific antibody is about 100 mg or about 300 mg.

7. The method of any one of claims 1 -6, wherein the length of the first dosing cycle is about 21 days.

8. The method of claim 7, wherein the Cycle 1 , Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the first dosing cycle.

9. The method of any one of claims 1 -8, wherein the dosing regimen comprises one or more additional dosing cycles.

10. The method of claim 9, wherein the dosing regimen comprises one to six additional dosing cycles.11 . The method of claim 9 or 10, wherein the length of each of the one or more additional dosing cycles is about 21 days.

12. The method of any one of claims 9-11 , wherein each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody.

13. The method of claim 12, wherein each single dose of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 1 of the bispecific antibody.

14. The method of claim 12 or 13, wherein each single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

15. A method of treating a subject having a cell proliferative disorder, the method comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:(a) the first dosing cycle comprises a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher in amount than the Cycle 1 , Dose 1 of the bispecific antibody; and(b) the second dosing cycle comprises a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody.

16. The method of claim 15, wherein the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg or about 1 .8 mg and the Cycle 1 , Dose 2 of the bispecific antibody is about 3 mg.

17. The method of claim 15, wherein:(a) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg;(b) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg;(c) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg;(d) the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg;(e) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg; or(f) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg.

18. The method of any one of claims 15-17, wherein the length of the first dosing cycle is about 21 days.

19. The method of claim 18, wherein the Cycle 1 , Dose 1 and the Cycle 1 , Dose 2 of the bispecific antibody are administered to the subject on about Day 1 and about Day 8, respectively, of the first dosing cycle.

20. The method of any one of claims 15-19, wherein the length of the second dosing cycle is about 21 days.21 . The method of claim 20, wherein the Cycle 2, Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the second dosing cycle.

22. The method of any one of claims 15-21 , wherein the dosing regimen comprises one or more additional dosing cycles.

23. The method of claim 22, wherein the dosing regimen comprises one to six additional dosing cycles.

24. The method of claim 22 or 23, wherein the length of each of the one or more additional dosing cycles is about 21 days.

25. The method of any one of claims 22-24, wherein each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody.

26. The method of claim 25, wherein each single dose of the bispecific antibody is about equivalent in amount to the Cycle 2, Dose 1 of the bispecific antibody.

27. The method of claim 25 or 26, wherein each single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

28. A method of treating a subject having a cell proliferative disorder, the method comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 and an effective amount of atezolizumab in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises:(a) a single dose (Cycle 1 , Dose 1 ) of the bispecific antibody; and(b) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg.

29. The method of claim 28, wherein the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg, from about 0.9 mg to about 100 mg, or from about 100 mg to about 300 mg.

30. The method of claim 28, wherein the Cycle, Dose 1 of the bispecific antibody is about 0.9 mg, about 100 mg, or about 300 mg.31 . The method of any one of claims 28-30, wherein the length of the first dosing cycle is about 21 days.

32. The method of claim 31 , wherein the Cycle 1 , Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the first dosing cycle.

33. The method of claim 31 or 32, wherein the Cycle 1 , Dose 1 of atezolizumab is administered to the subject on about Day 1 of the first dosing cycle.

34. The method of any one of claims 28-33, wherein the Cycle 1 , Dose 1 of the bispecific antibody and the Cycle 1 , Dose 1 of atezolizumab are administered to the subject on about the same day in the first dosing cycle.

35. The method of any one of claims 28-34, wherein the dosing regimen comprises one or more additional dosing cycles.

36. The method of claim 35, wherein the dosing regimen comprises one to six additional dosing cycles.

37. The method of claim 35 or 36, wherein the length of each of the one or more additional dosing cycles is about 21 days.

38. The method of any one of claims 35-37, wherein each of the one or more additional dosing cycles comprises:(a) a single dose of the bispecific antibody; and(b) a single dose of atezolizumab, wherein the single dose of atezolizumab is about 1200 mg.

39. The method of claim 38, wherein each single dose of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 1 of the bispecific antibody.

40. The method of claim 38 or 39, wherein the single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.41 . The method of any one of claims 38-40, wherein the single dose of atezolizumab is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

42. The method of any one of claims 38-41 , wherein the single dose of the bispecific antibody and the single dose of atezolizumab are administered to the subject on about the same day in each of the one or more additional dosing cycles.

43. A method of treating a subject having a cell proliferative disorder, the method comprising administering to the subject an effective amount of a bispecific antibody that binds CCR8 and CD3 and aneffective amount of atezolizumab in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:(a) the first dosing cycle comprises:(i) a first dose (Cycle 1 , Dose 1 ) and a second dose (Cycle 1 , Dose 2) of the bispecific antibody, wherein the Cycle 1 , Dose 2 of the bispecific antibody is higher than the Cycle 1 , Dose 1 of the bispecific antibody; and(ii) a single dose (Cycle 1 , Dose 1 ) of atezolizumab, wherein the Cycle 1 , Dose 1 of atezolizumab is about 1200 mg; and(b) the second dosing cycle comprises:(i) a single dose (Cycle 2, Dose 1 ) of the bispecific antibody, wherein the Cycle 2, Dose 1 of the bispecific antibody is about equivalent in amount to the Cycle 1 , Dose 2 of the bispecific antibody; and(ii) a single dose (Cycle 2, Dose 1 ) of atezolizumab, wherein the Cycle 2, Dose 1 of atezolizumab is about 1200 mg.

44. The method of claim 43, wherein the Cycle 1 , Dose 1 of the bispecific antibody is about 0.9 mg or about 1 .8 mg and the Cycle 1 , Dose 2 of the bispecific antibody is about 3 mg.

45. The method of claim 43, wherein:(a) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 100 mg;(b) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg;(c) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 0.9 mg to about 300 mg;(d) the Cycle 1 , Dose 1 of the bispecific antibody is from about 100 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg;(e) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 100 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg; or(f) the Cycle 1 , Dose 1 of the bispecific antibody is from about 0.9 mg to about 300 mg and the Cycle 1 , Dose 2 of the bispecific antibody is from about 100 mg to about 300 mg.

46. The method of any one of claims 43-45, wherein the length of the first dosing cycle is about 21 days.

47. The method of claim 46, wherein the Cycle 1 , Dose 1 and the Cycle 1 , Dose 2 of the bispecific antibody are administered to the subject on about Day 1 and about Day 8, respectively, of the first dosing cycle.

48. The method of claim 46 or 47, wherein the Cycle 1 , Dose 1 of atezolizumab is administered to the subject on about Day 1 of the first dosing cycle.

49. The method of any one of claims 43-48, wherein the Cycle 1 , Dose 1 of the bispecific antibody and the Cycle 1 , Dose 1 of atezolizumab are administered to the subject on about the same day in the first dosing cycle.

50. The method of any one of claims 43-49, wherein the length of the second dosing cycle is about 21 days.51 . The method of claim 50, wherein the Cycle 2, Dose 1 of the bispecific antibody is administered to the subject on about Day 1 of the second dosing cycle.

52. The method of claim 50 or 51 , wherein the Cycle 2, Dose 1 of atezolizumab is administered to the subject on about Day 1 of the second dosing cycle.

53. The method of any one of claims 43-52, wherein the Cycle 2, Dose 1 of the bispecific antibody and the Cycle 2, Dose 1 of atezolizumab are administered to the subject on about the same day in the second dosing cycle.

54. The method of any one of claims 43-53, wherein the dosing regimen comprises one or more additional dosing cycles.

55. The method of claim 54, wherein the dosing regimen comprises one to six additional dosing cycles.

56. The method of claim 54 or 55, wherein the length of each of the one or more additional dosing cycles is about 21 days.

57. The method of any one of claims 54-56, wherein each of the one or more additional dosing cycles comprises:(a) a single dose of the bispecific antibody; and(b) a single dose of atezolizumab, wherein the single dose of atezolizumab is about 1200 mg.

58. The method of claim 57, wherein each single dose of the bispecific antibody is about equivalent in amount to the Cycle 2, Dose 1 of the bispecific antibody.

59. The method of claim 57 or 58, wherein the single dose of the bispecific antibody is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.

60. The method of any one of claims 57-59, wherein the single dose of atezolizumab is administered to the subject on about Day 1 of each of the one or more additional dosing cycles.61 . The method of any one of claims 57-60, wherein the single dose of the bispecific antibody and the single dose of atezolizumab are administered to the subject on about the same day in each of the one or more additional dosing cycles.

62. The method of any one of claims 28-61 , wherein atezolizumab is administered intravenously.

63. The method of any one of claims 28-62, wherein when the bispecific antibody and atezolizumab are administered on about the same day, the bispecific antibody is administered at least 30 minutes after the end of the administration of atezolizumab.

64. The method of any one of claims 28-63, wherein when the bispecific antibody and atezolizumab are administered on about the same day, the bispecific antibody is administered at least 60 minutes after the end of the administration of atezolizumab.

65. The method of any one of claims 1 -64, wherein the bispecific antibody is administered intravenously.

66. The method of any one of claims 1 -62, 64, and 65, further comprising administering to the subject an effective amount of a corticosteroid.

67. The method of claim 66, wherein the corticosteroid is dexamethasone or methylprednisolone.

68. The method of claim 67, wherein:(a) the corticosteroid is dexamethasone, and wherein dexamethasone is administered at a dose of about 20 mg; or(b) the corticosteroid is methylprednisolone, and wherein methylprednisolone is administered at a dose of about 80 mg.

69. The method of any one of claims 66-68, wherein the corticosteroid is administered about one hour prior to the start of the administration of any dose of the bispecific antibody in the first dosing cycle.

70. The method of any one of claims 66-69, wherein when the bispecific antibody, atezolizumab, and the corticosteroid are administered on about the same day, the corticosteroid is administered at least 60 minutes after the end of the administration of atezolizumab and about one hour prior to the start of the administration of the bispecific antibody.71 . The method of any one of claims 66-70, wherein the subject experiences cytokine release syndrome (CRS), infusion-related reaction (IRR), or immune effector cell-associated neurotoxicitysyndrome (ICANS) in a dosing cycle, and wherein the corticosteroid is administered about one hour prior to the start of the administration of the bispecific antibody in the next dosing cycle.

72. The method of any one of claims 66-71 , further comprising administering to the subject an effective amount of tocilizumab.

73. The method of claim 72, wherein tocilizumab is administered at a dose of about 8 mg / kg or about 12 mg / kg.

74. The method of any one of claims 1 -73, wherein the subject experiences CRS after being administered the bispecific antibody, and wherein:(a) dexamethasone is administered to the subject about every 6 hours; or(b) tocilizumab and dexamethasone are administered to the subject about every 6 hours.

75. The method of claim 74, wherein dexamethasone is administered at a dose of about 10 mg; and / or wherein tocilizumab is administered at a dose of about 8 mg / kg or about 12 mg / kg.

76. The method of any one of claims 72-75, wherein tocilizumab is administered intravenously.

77. The method of any one of claims 66-76, wherein the corticosteroid is administered intravenously.

78. The method of any one of claims 1 -77, further comprising administering to the subject an effective amount of an antihistamine.

79. The method of claim 78, wherein the antihistamine is diphenhydramine.

80. The method of claim 79, wherein diphenhydramine is administered at a dose of from about 25 mg to about 50 mg.81 . The method of any one of claims 78-80, wherein the antihistamine is administered at least about 30 minutes prior to the start of the administration of any dose of the bispecific antibody.

82. The method of any one of claims 78-81 , wherein the antihistamine is administered orally.

83. The method of any one of claims 1 -82, further comprising administering to the subject an effective amount of acetaminophen (paracetamol).

84. The method of claim 83, wherein acetaminophen (paracetamol) is administered at a dose of from about 500 mg to about 1 ,000 mg.

85. The method of claim 83 or 84, wherein acetaminophen (paracetamol) is administered at least about 30 minutes prior to the start of the administration of any dose of the bispecific antibody.

86. The method of any one of claims 83-85, wherein acetaminophen (paracetamol) is administered orally.

87. The method of any one of claims 1 -86, wherein the bispecific antibody comprises:(a) a first antigen-binding domain that binds CCR8, wherein the first antigen-binding domain comprises the following six complementarity-determining regions (CDRs):(i) a heavy chain CDR 1 (CDR-H1 ) comprising the amino acid sequence TYAMG (SEQ ID NO: 1 );(ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO: 2);(Hi) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3);(iv) a light chain CDR 1 (CDR-L1 ) comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4);(v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and(vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6);(b) a second antigen-binding domain that binds CD3, wherein the second antigen-binding domain comprises the following six CDRs:(i) a CDR-H1 comprising the amino acid sequence NYYIH (SEQ ID NO: 7);(ii) a CDR-H2 comprising the amino acid sequence WIYPGDGNTKYNEKFKG (SEQ ID NO:8);(Hi) a CDR-H3 comprising the amino acid sequence DSYSNYYFDY (SEQ ID NO: 9);(iv) a CDR-L1 comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 10);(v) a CDR-L2 comprising the amino acid sequence WASTRES (SEQ ID NO: 11 ); and(vi) a CDR-L3 comprising the amino acid sequence TQSFILRT (SEQ ID NO: 12); and(c) a third antigen-binding domain that binds CCR8, wherein the third antigen-binding domain comprises the following six CDRs:(i) a CDR-H1 comprising the amino acid sequence TYAMG (SEQ ID NO: 1 );(ii) a CDR-H2 comprising the amino acid sequence LIHRSGRTYYATWAKG (SEQ ID NO:2);(Hi) a CDR-H3 comprising the amino acid sequence SYPDYSATASI (SEQ ID NO: 3);(iv) a CDR-L1 comprising the amino acid sequence QASENIANALA (SEQ ID NO: 4);(v) a CDR-L2 comprising the amino acid sequence GASNLAS (SEQ ID NO: 5); and(vi) a CDR-L3 comprising the amino acid sequence QQAYYGNSFVEGT (SEQ ID NO: 6).

88. The method of claim 87, wherein the first antigen-binding domain comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, and wherein:(a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); and / or(b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat).

89. The method of claim 87 or 88, wherein the second antigen-binding domain comprises a VL domain and a VH domain, and wherein the VL domain comprises a glutamic acid residue at position 38 and the VH domain comprises a lysine residue at position 39 (numbering according to Kabat).

90. The method of any one of claims 87-89, wherein the third antigen-binding domain comprises a VL domain and a VH domain, and wherein:(a) the VL domain comprises a proline residue at position 12 (numbering according to Kabat); and / or(b) the VL domain comprises a lysine residue at position 38 and the VH domain comprises a glutamic acid residue at position 39 (numbering according to Kabat).91 . The method of any one of claims 87-90, wherein:(a) the first antigen-binding domain comprises:(i) a VH domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 13;(ii) a VL domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 14; or(Hi) a VH domain as in (i) and a VL domain as in (ii);(b) the second antigen-binding domain comprises:(i) a VH domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 15;(ii) a VL domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 16; or(Hi) a VH domain as in (i) and a VL domain as in (ii); and / or(c) the third antigen-binding domain comprises:(i) a VH domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 13;(ii) a VL domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 14; or(Hi) a VH domain as in (i) and a VL domain as in (ii).

92. The method of claims 91 , wherein:(a) the first antigen-binding domain comprises:(i) a VH domain comprising the amino acid sequence of SEQ ID NO: 13;(ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 14; or (Hi) a VH domain as in (i) and a VL domain as in (ii);(b) the second antigen-binding domain comprises:(i) a VH domain comprising the amino acid sequence of SEQ ID NO: 15;(ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 16; or(iii) a VH domain as in (i) and a VL domain as in (ii); and / or(c) the third antigen-binding domain comprises:(i) a VH domain comprising the amino acid sequence of SEQ ID NO: 13;(ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 14; or(iii) a VH domain as in (i) and a VL domain as in (ii).

93. The method of any one of claims 87-92, wherein each of the first, the second, and / or the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain.

94. The method of claim 93, wherein each of the first, the second, and the third antigen-binding domain is a Fab molecule comprising a Fab light chain and a Fab heavy chain, and wherein:(a) the Fab light chain of the first antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the first antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat);(b) the Fab light chain of the second antigen-binding domain comprises a lysine residue at position 133, and the Fab heavy chain of the second antigen-binding domain comprises a glutamic acid residue at position 183 (numbering according to Kabat); and / or(c) the Fab light chain of the third antigen-binding domain comprises a glutamic acid residue at position 133, and the Fab heavy chain of the third antigen-binding domain comprises a lysine residue at position 183 (numbering according to Kabat).

95. The method of any one of claims 87-94, wherein the second antigen-binding domain and the third antigen-binding domain are fused to each other.

96. The method of claim 95, wherein the second antigen-binding domain and the third antigenbinding domain are fused to each other via a peptide linker.

97. The method of claim 96, wherein the peptide linker comprises the amino acid sequence of SEQ ID NO: 21.

98. The method of any one of claims 95-97, wherein each of the second antigen-binding domain and the third antigen-binding domain is a Fab molecule, and wherein the third antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigenbinding domain.

99. The method of any one of claims 87-98, wherein the bispecific antibody further comprises an Fc domain comprising a first subunit and a second subunit.

100. The method of claim 99, wherein the Fc domain is an IgG Fc domain.101 . The method of claim 100, wherein the Fc domain is an IgG 1 Fc domain.

102. The method of any one of claims 99-101 , wherein the Fc domain is a human IgG Fc domain.

103. The method of any one of claims 99-102, wherein the Fc domain comprises a modification promoting the association of the first subunit and the second subunit of the Fc domain.

104. The method of any one of claims 99-103, wherein each of the first and the second subunit comprises an alanine residue at position 234, an alanine residue at position 235, and a glycine residue at position 329 (numbering according to Kabat EU index).

105. The method of any one of claims 87-104, wherein the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH2i) domain, a first CH3 (CH3i) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain.

106. The method of any one of claims 99-104, wherein the first subunit comprises one or more heavy chain constant domains selected from a first CH2 (CH2i) domain and / or a first CH3 (CH3i) domain; and the second subunit comprises one or more heavy chain constant domains selected from a second CH2 (CH22) domain and / or a second CH3 (CH32) domain.

107. The method of claim 106, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

108. The method of claim 107, wherein each of the CH3i and CH32 domains comprises a protuberance or cavity, and wherein the protuberance or cavity in the CH3i domain is positionable in the cavity or protuberance, respectively, in the CH32 domain.

109. The method of claim 108, wherein the CH3i and CH32 domains meet at an interface between said protuberance and cavity.

110. The method of any one of claims 106-109, wherein the CH2i and CH22 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2i domain is positionable in the cavity or protuberance, respectively, in the CH22 domain.

111. The method of claim 110, wherein the CH2i and CH22 domains meet at an interface between said protuberance and cavity.

112. The method of any one of claims 109-111 , wherein:(a) the first subunit comprises a tryptophan residue at position 366 (numbered according to Kabat EU index); and(b) the second subunit comprises a serine residue at position 366, an alanine residue at position 368, and a valine residue at position 407 (numbered according to Kabat EU index).

113. The method of any one of claims 93-112, wherein each of the first antigen-binding domain and the second antigen-binding domain is a Fab molecule, wherein the bispecific antibody comprises an Fc domain comprising a first subunit and a second subunit, and wherein:(a) the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the first subunit; and(b) the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the second subunit.

114. The method of any one of claims 93-113, wherein each of the first, the second, and the third antigen-binding domain is a Fab molecule, wherein the bispecific antibody comprises an Fc domain comprising a first subunit and a second subunit, and wherein:(a) the first antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the first subunit;(b) the second antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the second subunit; and(c) the third antigen-binding domain is fused at the C-terminus of the Fab heavy chain to the N- terminus of the Fab heavy chain of the second antigen-binding domain.

115. The method of any one of claims 87-114, wherein the bispecific antibody comprises:(a) a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 17;(b) a first polypeptide and a second polypeptide each comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 18;(c) a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 19; and(d) a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 20.

116. The method of claim 115, wherein the bispecific antibody comprises:(a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 17;(b) a first polypeptide and a second polypeptide each comprising the amino acid sequence of SEQID NO: 18;(c) a polypeptide comprising the amino acid sequence of SEQ ID NO: 19; and(d) a polypeptide comprising the amino acid sequence of SEQ ID NO: 20.

117. The method of any one of claims 1 -116, wherein the subject is a human.

118. The method of any one of claims 1 -117, wherein:(a) the subject has progressed after at least one available standard therapy; and / or(b) the subject is one for whom all available standard therapy has been proven to be ineffective or intolerable or is contraindicated.

119. The method of any one of claims 1 -118, wherein the subject’s age is 18 years or older.

120. The method of any one of claims 1 -119, wherein the cell proliferation disorder is a cancer.121 . The method of any one of claims 1 -120, wherein the cell proliferation disorder is a solid tumor malignancy.

122. The method of any one of claims 1 -121 , wherein the cell proliferation disorder is a locally advanced, recurrent, or metastatic incurable solid tumor malignancy.

123. The method of any one of claims 1 -121 , wherein the cell proliferation disorder is selected from the group consisting of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), cutaneous melanoma, triple-negative breast cancer (TNBC), urothelial carcinoma (UCC), esophageal cancer, gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, clear cell renal cell carcinoma (ccRCC), and hepatocellular carcinoma (HCC).

124. The method of any one of claims 1 -123, wherein the subject is checkpoint inhibitor (CPI)-naTve.

125. The method of claim 124, wherein the cell proliferation disorder is NSCLC, and wherein the subject has a tumor cell (TC) PD-L1 expression of > 50%, or an immune cell (IC) PD-L1 expression of > 10%.

126. The method of claim 124, wherein the cell proliferation disorder is HNSCC, and wherein the subject has a combined TC / IC PD-L1 expression of > 20.

127. The method of claim 124, wherein the cell proliferation disorder is HNSCC, and wherein the subject has a combined TC / IC PD-L1 expression of > 1 and < 19.

128. The method of claim 126 or 127, wherein the combined TC / IC PD-L1 expression is determined as tumor area positivity (TAP) or combined positive score (CPS).

129. The method of claim 124, wherein the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 20%.

130. The method of claim 124, wherein the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 5% to > 19%.131 . The method of any one of claims 1 -123, wherein the subject is CPI-experienced.

132. The method of claim 131 , wherein the cell proliferation disorder is NSCLC, HNSCC, gastric cancer, GEJ adenocarcinoma, HCC, ccRCC, TNBC, or UCC, and wherein the subject has a TC, IC, or combined TC / IC PD-L1 expression of > 1 or 1%.

133. The method of claim 131 , wherein the cell proliferation disorder is esophageal cancer, and wherein the subject has a TC, IC, or combined TC / IC PD-L1 expression of > 10 or 10%.

134. The method of claim 132 or 133, wherein the combined TC / IC PD-L1 expression is determined as CPS, TAP, or tumor proportion score (TPS).

135. The method of claim 131 , wherein the cell proliferation disorder is NSCLC, and wherein the subject has an IC PD-L1 expression of > 1%.

136. The method of claim 131 , wherein the cell proliferation disorder is HNSCC, and wherein the subject has a PD-L1 TAP of > 5%.

137. The method of claim 131 , wherein the cell proliferation disorder is gastric cancer or GEJ adenocarcinoma, and wherein the subject has a PD-L1 TAP of > 1%.

138. The method of claim 131 , wherein the cell proliferation disorder is ccRCC, TNBC, or UCC, and wherein the subject has an IC PD-L1 expression of > 1%.

139. The method of claim 131 , wherein the cell proliferation disorder is esophageal cancer, and wherein the subject has a PD-L1 TAP of > 10%.

140. The method of claim 123, wherein the cell proliferative disorder is NSCLC or HNSCC.141 . The method of claim 140, wherein the HNSCC is HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx.

142. The method of any one of claims 121 -141 , wherein the subject’s tumor comprises a targetable somatic alteration, and the subject has experienced disease progression during or after treatment, or intolerance to treatment, with a targeted agent.

143. The method of claim 142, wherein the targetable somatic alteration comprises a somatic alteration involving epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1 ), proto-oncogene B-Raf (BRAF) V600E, neurotrophic tyrosine receptor kinase (NTRK), MET proto-oncogene (MET), RET proto-oncogene (RET), or Kirsten rat sarcoma virus (KRAS).

144. The method of claim 123, wherein the cell proliferation disorder is cutaneous melanoma, wherein the subject’s tumor comprises a BRAFV600 mutation, and wherein the subject has experienced disease progression during or after treatment, or intolerance to treatment, with one or more serine / threonine- protein kinase B-Raf (BRAF) inhibitors and / or one or more mitogen-activated protein kinase kinase (MEK) inhibitors.

145. The method of any one of claims 1 -144, further comprising determining the expression level of programmed death-ligand 1 (PD-L1 ) in a sample obtained from the subject.

146. The method of claim 145, wherein the sample is a tumor sample.

147. The method of claim 145 or 146, wherein the sample is a fresh tumor sample, a formalin-fixed, paraffin-embedded tumor sample, or an archival tumor sample.

148. The method of any one of claims 145-147, wherein the sample comprises tumor cells, tumor infiltrating immune cells, stromal cells, and any combinations thereof.

149. The method of any one of claims 145-148, wherein the sample is obtained prior to the first dosing cycle.

150. The method of any one of claims 145-149, wherein PD-L1 is absent from the sample when it comprises 0% of the sample.151 . The method of any one of claims 145-150, wherein PD-L1 is present in the sample when it comprises more than 0% of the sample.

152. The method of claim 151 , wherein PD-L1 is expressed in tumor cells covering at least 1 % of the tumor sample area.

153. The method of claim 151 , wherein PD-L1 is expressed in tumor cells covering at least 5% of the tumor sample area.

154. The method of claim 151 , wherein PD-L1 is expressed in tumor cells covering at least 10% of the tumor sample area.

155. The method of claim 151 , wherein PD-L1 is expressed in tumor cells covering at least 20% of the tumor sample area.

156. The method of claim 151 , wherein PD-L1 is expressed in tumor cells covering at least 50% of the tumor sample area.

157. The method of claim 151 , wherein PD-L1 is expressed in tumor-infiltrating immune cells covering at least 1% of the tumor sample area.

158. The method of claim 151 , wherein PD-L1 is expressed in tumor-infiltrating immune cells covering at least 5% of the tumor sample area.

159. The method of claim 151 , wherein PD-L1 is expressed in tumor-infiltrating immune cells covering at least 10% of the tumor sample area.

Images