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Dosing regimen for gp100-specific tcr-Anti-cd3 scfv fusion protein

A bispecific and dosing technology, which is applied to the dosage regimen of T cell redirecting bispecific therapeutic agents and the treatment of gp100-positive cancers, can solve the problems of not being able to predict the appropriate therapeutic dose of T cell redirecting therapeutic agents a priori, etc. Achieve the effect of improving clinical curative effect and improving clinical curative effect

Active Publication Date: 2019-06-28
IMMUNOCORE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, although many gp100-specific vaccines and autologous T-cell therapies are known to have on-target off-tumor toxicity that have been evaluated in the clinic, appropriate therapeutic doses of T-cell redirecting therapeutics cannot be predicted a priori

Method used

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  • Dosing regimen for gp100-specific tcr-Anti-cd3 scfv fusion protein
  • Dosing regimen for gp100-specific tcr-Anti-cd3 scfv fusion protein
  • Dosing regimen for gp100-specific tcr-Anti-cd3 scfv fusion protein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Example 1 - Identification of a Dosage Regimen for IMCgp100 that Ameliorates Drug-Associated Severe Hypotension and Allows Raising the Dose Upper Limit

[0118] IMCgp100 is a T cell redirecting bispecific reagent comprising an affinity-enhanced soluble TCR bound to a YLEPGPVTA peptide-HLA-A*02 complex fused to an anti-CD3 scFv.

[0119] [The alpha and beta chains of IMCgp100 are SEQ ID NO:4 and 5, respectively] IMCgp100 was investigated in a first-in-human (FIH) open-label dose-finding study to evaluate the safety and resistance of IMCgp100 in patients with advanced malignant melanoma Acceptability (Clinical Trial Identifier: NCT01211262). The study was designed to determine the maximum tolerated dose (MTD) or phase II recommended dose (RP2D) of IMCgp100 in 2 repeat dosing regimens: (Arm 1) weekly dosing (RP2D-QW) and (Arm2) daily dosing Medication × 4 days (RP2D-QD).

[0120] Patients with stage IV or unresectable stage III malignant melanoma participated in the stud...

Embodiment 2-I

[0140] Example 2 - Evidence of an Increased Risk of Severe Hypotension Caused by Combination Administration of IMCgp100 and Other Immunomodulatory Drugs

[0141] IMCgp100-mediated immune activation was studied in vitro in the presence or absence of checkpoint inhibitor antibodies against PD-L1 / PD-1 and CTLA-4.

[0142] Combination of IMCgp100 and anti-CTLA-4 increases the potency of T cell responses

[0143] In this experiment, T cell proliferation was used as potency readout. IMCgp100 was used at a concentration of 80 pM in the presence or absence of 40 ug / ml anti-CTLA-4 (clone L3D10; Biolegend). HLA-A*02-positive monocytes pulsed with 10 nM or 100 nM gp100 peptide were used as target antigen-presenting cells and plated at 10,000 cells / well. Effector CD3+ T cells were labeled with CellTracker Violet. After 5 days, T cell proliferation was measured using a FACS-based Intellicyt assay.

[0144] Figure 7 The results presented in show that IMCgp100 in combination with anti-...

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Abstract

The present disclosure relates to the treatment of cancer, particularly gp100 positive cancers. In particular, it relates to a dosage regimen for a T cell redirecting bispecific therapeutic comprisinga targeting moiety that binds the YLEPGPVTA-HcLA-A2 complex fused to a CD3 binding T cell redirecting moiety.

Description

technical field [0001] The present invention relates to the treatment of cancer, in particular to the treatment of gp100 positive cancer. In particular, the present invention relates to a dosage regimen of a T cell redirecting bispecific therapeutic agent comprising a targeting moiety that binds to the YLEPGPVTA-HLA-A2 complex, the targeting moiety binds to CD3 Redirected partial fusion of T cells. Background technique [0002] Human glycoprotein 100 (gp100) is one of the melanoma-associated antigen groups, and the body can generate a natural immune response to melanoma-associated antigens. This protein is a 661 amino acid melanosomal membrane-associated glycoprotein expressed in normal melanocytes and widely overexpressed in most melanoma cancer cells. For example, one study (Trefzer et al., (2006) Melanoma Res. 16(2):137-45) found that 82% of 192 melanoma metastases from 28 melanoma patients expressed gplOO. Some studies have reported a higher expression level of gp100 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/30A61P35/00C07K16/28C07K14/705A61K38/17A61K39/395
CPCA61K38/177C07K14/70503C07K16/28C07K16/2809C07K16/2818C07K16/2827C07K16/3053A61K2039/505A61K2039/507A61K2039/545C07K2317/31C07K2317/34C07K2317/622C07K2319/00A61P35/00C07K16/2833C07K2317/32A61K39/3955C07K14/7051A61K31/4439A61K38/1774C07K2317/76C07K2319/30
Inventor 克里斯蒂娜·科格林
Owner IMMUNOCORE LTD