Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10682365-B2
Publication Date
2020-06-16
Expiration Date
Abstract
Provided are methods for treating cancer using local administration of certain CpG oligonucleotides (CpG ODN) and systemic administration of a checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, and/or an anti-CTLA-4 antibody. In preferred embodiments, the CpG ODN are selected based on their propensity to induce high amounts of interferon alpha (IFN-α) and T-cell activation relative to interleukin-10 (IL-10) and B-cell activation. In certain embodiments, the methods further include pretreatment with radiotherapy, to potentiate the combination immunotherapy.
Core Innovation
The invention relates to combination tumor immunotherapy using a TLR9 agonist and a checkpoint inhibitor (CPI). A TLR9 agonist is administered intratumorally or peritumorally to a subject in need thereof for treating a cancerous tumor, and the checkpoint inhibitor is administered together with the TLR9 agonist as part of the treatment regimen.
The TLR9 agonist is specifically an A-class CpG DNA of SEQ ID NO:82. The CPI is an antibody or an antigen-binding fragment thereof that binds specifically to an antigen selected from PD-1, PD-L1, CTLA-4, TIM3, LAG3, and BTLA.
The described concept emphasizes selection of CpG ODN classes that preferentially induce high type I interferon (IFN-α) and T-cell activation while reducing IL-10 and B-cell activation by altering CpG ODN backbone or structure. The disclosure also provides CpG ODN sequence and backbone design options, including labeled nucleotides and internucleotide linkages such as phosphodiester, phosphorothioate, phosphorodithioate, 2′-O-methyl nucleotides, and halogenated uracils.
The disclosure introduces “soft” and “semi-soft” oligonucleotide backbone concepts and describes non-limiting optimization considerations for CpG-A and A/E-class designs, including effects of G-tetrad/polyG termini, palindrome effects, and PS linkage count and chirality. It also connects these design concepts to cancer immunotherapy contexts involving TLR9 agonists and checkpoint inhibitor antibodies, including in vitro PBMC data sets and an in vivo A20 lymphoma study with synergistic efficacy and improved survival.
Claims Coverage
The independent claim coverage centers on treating a cancerous tumor by administering an effective amount of a TLR9 agonist and a CPI, with intratumoral or peritumoral delivery of the TLR9 agonist, where the TLR9 agonist is an A-class CpG DNA of SEQ ID NO:82 and the CPI binds specified checkpoint antigens. The coverage includes three inventive features.
Intratumoral or peritumoral TLR9 agonist with checkpoint inhibitor combination
Administering to a subject in need thereof an effective amount of a TLR9 agonist and a checkpoint inhibitor (CPI), wherein the TLR9 agonist is administered intratumorally or peritumorally, and the CPI is an antibody or antigen-binding fragment thereof.
A-class CpG DNA of SEQ ID NO:82 as the TLR9 agonist
Administering the TLR9 agonist as an A-class CpG DNA of SEQ ID NO:82.
Checkpoint inhibitor binding to selected checkpoint antigens
Using a CPI that binds specifically to an antigen selected from the group consisting of PD-1, PD-L1, CTLA-4, TIM3, LAG3, and BTLA.
Overall claim coverage centers on local delivery of an A-class CpG DNA TLR9 agonist of SEQ ID NO:82 combined with a CPI antibody or antigen-binding fragment that specifically targets PD-1, PD-L1, CTLA-4, TIM3, LAG3, or BTLA.
Stated Advantages
More sustained TLR9 signal for IFN-α induction.
Limits B-cell and IL-10 activation.
Synergistic efficacy of intratumoral CpG-A with systemic anti-PD-1.
Improved survival in the A20 lymphoma study.
Preferentially induce high type I interferon (IFN-α) and T-cell activation while reducing IL-10 and B-cell activation.
Documented Applications
Treating a cancerous tumor by administering a TLR9 agonist (A-class CpG DNA of SEQ ID NO:82) and a checkpoint inhibitor antibody or antigen-binding fragment.
In vivo A20 lymphoma treatment context using intratumoral CpG-A with systemic anti-PD-1, including improved survival and synergy.
In vitro PBMC cytokine reporting context measuring IFN-α and IL-10 secretion following CpG ODN design and formulation-related conditions.
Interested in licensing this patent?