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Dose regimen for administration of LAG-3/PD-L1 bispecific antibodies

A technology of PD-L1 and LAG-3, applied in the direction of antibodies, antibody medical components, specific peptides, etc., can solve the problems that LAG-3/PD-L1 antibodies have not yet been obtained

Pending Publication Date: 2022-03-18
F STAR THERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] No data are available to date on the properties of LAG-3 / PD-L1 antibodies, including FS118, in human patients or nonhuman primates, including doses administered

Method used

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  • Dose regimen for administration of LAG-3/PD-L1 bispecific antibodies
  • Dose regimen for administration of LAG-3/PD-L1 bispecific antibodies
  • Dose regimen for administration of LAG-3/PD-L1 bispecific antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] Example 1: First in human (FIH) dose justification and dose escalation strategy for FS118 slightly

[0219] FS118 is a bispecific antibody molecule that simultaneously targets two immune checkpoint proteins, LAG-3 and PD-L1. FS118 has been shown to differ from monospecific immune checkpoint inhibitors, such as anti-PD-L1 antibodies, in a number of important ways. These differences require detailed analysis to determine the appropriate dose for Phase I studies of FS118 in human patients. Specifically, FS118 was tested in in vitro and in vivo studies to determine the optimal starting dose and dose escalation strategy for a phase I human study designed to determine the efficacy of FS118 in patients with previously PD-containing Safety, tolerability, pharmacokinetics and activity in patients with advanced malignancies who have progressed on or after 1 / PD-L1 therapy (see Example 2 below).

[0220] 1.1 FS118 and mLAG-3 / PD-L1: Overview of nonclinical studies

[0221] ...

Embodiment 2

[0330] Example 2: LAG-3 / PD-L1 bispecific antibody FS118 on or during prior PD-1 / PD-L1 containing therapy Phase I, open-label, safety, tolerability, pharmacokinetics, and activity in patients with advanced malignancies after progression Dose Escalation and Cohort Expansion First-in-Human Study

[0331] 2.1 Study Design and Parameters

[0332]Studies were conducted in adult patients diagnosed with advanced tumors to characterize the safety, tolerability, pharmacokinetics (PK) and activity of FS118. This phase I, multicenter, open-label, multiple-dose, first-in-human study was initiated with an accelerated titration design (over which a single patient cohort was evaluated) followed by a 3+3 ascending dose escalation design. The study was designed to systematically assess the safety and tolerability, maximum tolerated dose (MTD) and / or phase II recommended dose (RP2D) of FS118 in patients with confirmed advanced tumors. RP2D is defined as the maximum biologically effectiv...

Embodiment 3

[0490] Example 3: Selection of those more likely to respond to FS118 based on resistance to prior anti-PD-1 or anti-PD-L1 therapy patient

[0491] 3.1 Background

[0492] All patients included in the ongoing FS118 trial progressed on or after PD-1 / PD-L1-containing therapy.

[0493] Initial results (August 2019) demonstrated that FS118 was able to stabilize disease in some patients with a disease control rate (DCR) of 34.4% (see Example 2.3.1), rising to 47.2% as of April 2020 (see Implementation Example 2.4.1). The inventors hypothesized that FS118 could provide benefit to these patients due to the combination of a LAG-3 inhibitor with a PD-L1 inhibitor (dual checkpoint inhibitor) or by a PD-L1 and LAG-3 bispecific Additional benefits provided by targeting novel biology (WO2017220569A1). Patients are not expected to realize clinical benefit on retreatment with anti-PD-1 or anti-PD-L1-containing regimens alone (Fujita et al., Anticancer Res. (2019); Fujita et al., Thor...

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Abstract

The present application relates to dosage regimens for the administration of antibody molecules that bind programmed death-ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3) and their medical use in the treatment of cancer in human patients.

Description

technical field [0001] The present invention relates to dosage regimens for administration of antibody molecules that bind to programmed death-ligand 1 (PD-L1) and lymphocyte-activation gene 3 (LAG-3). dosage regimes) and their medical use in the treatment of cancer in human patients. The present invention also provides prognostic thresholds for predicting the likelihood that a human patient will respond to an antibody. Background technique [0002] Cancer is a complex disease for which there are still significant unmet needs. In recent years, the interaction between the host immune system and the tumor has become an area of ​​intense non-clinical and clinical assessment. Tumor infiltrating lymphocytes (TILs) have the ability to control tumor cell growth, and emerging clinical evidence suggests that patients with increased TILs have a favorable prognosis. Overall, T cells play a major role in immune defense against cancer and regulation of T cell activation is mediated by...

Claims

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Application Information

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IPC IPC(8): C07K16/46A61K39/395A61P35/00A61P35/02
CPCC07K16/2803C07K16/2827A61P35/00A61P35/02C07K2317/31C07K2317/76A61K2039/545A61K2039/505A61K2039/54C07K2317/56C07K2317/90
Inventor 米歇尔·莫罗菲奥纳·杰马斯切夫斯基丹尼尔·格利登梁健美克里斯蒂安·格拉迪纳鲁克里斯托弗·谢泼德约瑟芬-比特·霍尔茨露易丝·凯塔利尔
Owner F STAR THERAPEUTICS LTD
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