Dosing regimen of Anti-lag3 antibody and combination therapy with Anti-pd-1 antibody for treating cancer

A technology of PD-1 and PD-L1, which is applied to the dosing regimen in combination therapy to treat cancer in patients, and can solve problems such as releasing, stimulating cytokines, and affecting safety

Pending Publication Date: 2021-08-27
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, anti-LAG3 and / or anti-PD-1 / anti-PD-L1 therapy can lead to the possibility of immune stimulation and cytokine release, which affects safety

Method used

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  • Dosing regimen of Anti-lag3 antibody and combination therapy with Anti-pd-1 antibody for treating cancer
  • Dosing regimen of Anti-lag3 antibody and combination therapy with Anti-pd-1 antibody for treating cancer
  • Dosing regimen of Anti-lag3 antibody and combination therapy with Anti-pd-1 antibody for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0319] Example 1: Clinical research of anti-LAG3 antibody in advanced solid tumors

[0320] This is an anti-LAG3 antibody Ab6 monotherapy (Part A, arm 1) and Ab6 in combination with pembrolizumab (Part A, Multisite, open-label, dose-escalation study of arm 2), followed by nonrandomized and randomized dose confirmation of Ab6 in combination with pembrolizumab, as well as as monotherapy and in combination with pembrolizumab (Part B) Potency assessment of Ab6.

[0321] During Part A of the study, subjects were assigned by non-random assignment to 1 of 2 treatment groups:

[0322] Group 1 : Ab6 as monotherapy at escalating doses of 7, 21 , 70, 210 or 700 mg every 3 weeks (Q3W) via intravenous infusion (IV).

[0323] Arm 2: Ab6 at escalating doses of 7, 21, 70, 210, or 700 mg every 3 weeks (Q3W) IV in combination with pembrolizumab (200 mg Q3W) IV

[0324] Part B is the dose verification of Ab6 in combination with pembrolizumab. In addition, an expansion cohort evaluated the an...

Embodiment 2

[0356] Example 2: Pharmacokinetic (PK) studies of Ab6

[0357] PK data from subjects treated at doses ranging from 7 mg to 700 mg during Part A of Ab6 (Ab6 alone and in combination with pembrolizumab) showed a dose-dependent increase in serum Ab6 exposure ( Figure 5 ). Blood samples from patients were collected for PK analysis on days 1, 2, 8, 15 and 21 of Ab6 administration. The PK profile of Ab6 exposure indicated that target receptor-mediated clearance of Ab6 was saturated at doses of 210 mg and 700 mg ( Image 6 ).

[0358]Soluble (sLAG3) is a cleavage product of membrane-bound LAG3 expressed on immune cells. Cleavage of LAG3 is required for optimal T-cell function (Goldberg and Drake, LAG-3 in Cancer Immunotherapy; Dranoff G. (eds) Cancer Immunology and Immunotherapy (2010); Current Topics in Microbiology and Immunology, vol 344. Springer , Berlin, Heidelberg). sLAG is detectable in the serum of healthy patients and, to a greater extent, in patients with cancer and ...

Embodiment 3

[0369] Example 3: Measurement of PD-L1 and LAG3 expression levels

[0370] Samples from Part B of non-MSI-H colorectal cancer, gastric cancer and HNSCC patients were analyzed before treatment. The samples used for analysis were formalin-fixed and paraffin-embedded (FFPE) tissue sections. IHC staining for PD-L1 expression was performed using the Dako Autostainer Link 48 platform (Dako AS480) and an automated staining protocol validated for the PD-L1 IHC 22C3 pharmDx assay according to US2017 / 0285037 (which is incorporated by reference in its entirety). LAG-3 IHCAssay (LSBio, clone 17B4) was developed using 0.05 ug / ml clone 17B4 from LSBio and validated on a Dako Autostainer Link 48 platform according to the manufacturer's protocol. Formalin-fixed, paraffin-embedded 4-micron sections were used for the assay. Antigen retrieval was performed with Envision FLEX Target Retrieval Solution, High pH (Agilent K800221-2) on Dako PT link. For the detection system, Agilent EnVision FLEX...

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Abstract

The present invention relates to dosing regimens of an anti-LAG3 antibody useful for the treatment of cancer. In particular, the invention relates to the dosing regimen in a combination therapy which comprises administering an antibody of a Programmed Death 1 protein (PD-1) or Programmed Death Ligand 1 (PD-L1) and an antibody of Lymphocyte-Activation Gene 3 (LAG3). The invention also provides a method for treating cancer in a patient comprising administering to the patient an anti-LAG3 antibody and an anti-PD-1 antibody, wherein the tumor tissue section of the patient is PD-L1 expression positive, and optionally LAG3 expression positive.

Description

[0001] field of invention [0002] The present invention relates to dosing regimens of anti-LAG3 antibodies useful in the treatment of cancer. In particular, the present invention relates to dosing regimens in combination therapy comprising administration of antibodies to programmed death 1 protein (PD-1) or programmed death ligand 1 (PD-L1) and lymphocyte-activating gene 3 ( LAG3) antibody. The present invention also provides a method for treating cancer in a patient, comprising administering an anti-LAG3 antibody and an anti-PD-1 antibody to the patient, wherein the tumor tissue section of the patient is positive for PD-L1 expression, optionally The ground is positive for LAG3 expression. [0003] Background of the invention [0004] PD-1 is considered an important molecule in immune regulation and maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T, B and NKT cells and is upregulated through T / B cell receptor signaling on lymphocytes, monocytes an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/395
CPCA61P35/00C07K16/2803C07K16/2818A61K2039/505A61K2039/545A61K2039/507A61K2039/55A61K2039/54C07K2317/56A61K2300/00C07K2317/565C07K16/2827C07K2317/24
Inventor A·K·亚伯拉罕E·K·查塔什K·埃曼茨帕托尔R·加里多J·A·希利J·W·尤科D·莱维坦赵青
Owner MERCK SHARP & DOHME BV
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