Antibodies and nucleotide sequences, and uses thereof
Inventors
Frendéus, Björn • Teige, Ingrid • SEMMRICH, Monika • Mårtensson, Linda • HOLMKVIST, PETRA
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12291569-B2
Publication Date
2025-05-06
Expiration Date
Abstract
Described are novel anti-CTLA-4 antibody molecules and nucleotide sequences and expression vectors, such as viruses, encoding such antibody molecules. The novel antibody molecules are Treg depleting antibody molecules, and they have an improved depleting effect on CTLA-4 positive cells, such as Tregs, compared to ipilimumab. Described is also the use of such antibody molecules or nucleotide sequences or viruses in medicine, such as in the treatment of cancer, such as solid tumours.
Core Innovation
The invention relates to anti-CTLA-4 antibody molecules that specifically bind to CTLA-4 and are defined by six CDRs, including VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, with specified SEQ ID NOs. An alternate set of six CDRs with corresponding VH and VL CDR SEQ ID NOs is also described.
The disclosed antibodies are characterized by improved depleting effect on CTLA-4+FOXP3+ Tregs compared with ipilimumab. The document describes blocking of CTLA-4–B7.1 and CTLA-4–B7.2 while avoiding CD28 cross-reactivity, together with binding, blocking, and functional characterization and comparative evaluations.
The document further describes evaluation in vitro and in vivo for depletion readouts. In vitro ADCC is used for comparison, and in vivo depletion is assessed using PBMC-NOG/SCID models with FACS quantification for CTLA-4 positive cells, CD4 positive cells, and/or Tregs. The content also includes options for antibody formats, species-binding scope, and sequence definitions for nucleotide sequences, expression vectors/plasmids, and viruses, including oncolytic vaccinia expressing the antibody and optionally GM-CSF.
Claims Coverage
The independent claim coverage centers on an antibody molecule specifically binding to CTLA-4 and defined by six CDRs with specific SEQ ID NOs, with dependent claim refinements that narrow format, sequence identity, binding/cross-reactivity scope, and improved depletion criteria versus ipilimumab.
Six CDRs defined by SEQ ID NOs for CTLA-4 binding
An antibody molecule that specifically binds to CTLA-4, wherein the antibody molecule comprises the 6 CDRs having VH-CDR1 of SEQ ID NO: 15, the VH-CDR2 of SEQ ID NO: 16, the VH-CDR3 of SEQ ID NO: 17, the VL-CDR1 of SEQ ID NO: 10, the VL-CDR2 of SEQ ID NO: 18, and the VL-CDR3 of SEQ ID NO: 19, or comprises the 6 CDRs having VH-CDR1 of SEQ ID NO: 22, the VH-CDR2 of SEQ ID NO: 23, the VH-CDR3 of SEQ ID NO: 24, the VL-CDR1 of SEQ ID NO: 10, the VL-CDR2 of SEQ ID NO: 25, and the VL-CDR3 of SEQ ID NO: 26.
Improved depletion versus ipilimumab assessed by ADCC or PBMC-NOG/SCID depletion with FACS
A particular antibody molecule defined by the dependent claim includes an improved depleting effect on CTLA-4 positive cells, CD4 positive cells and/or Tregs compared to ipilimumab, as demonstrated by either an in vitro ADCC test with comparison of lysis results or by an in vivo PBMC-NOG/SCID model comparing depletion of CTLA-4 positive cells, CD4 positive cells and/or Tregs quantified by FACS.
Additional variable heavy chain and light chain constant region sequence identities
An antibody molecule includes specified variable heavy chain and/or variable light chain and/or specified heavy and light chain constant regions, identified by particular SEQ ID numbers.
Cross-species CTLA-4 binding and human CD28 non-binding
An antibody molecule binds to one or more of human CTLA-4, cynomolgus monkey CTLA-4, and murine CTLA-4, or alternatively does not bind to human CD28.
Selected antibody formats
The antibody molecule is chosen from monoclonal, full-size, chimeric, single-chain, Fab, Fv, scFv, FabⅡ, or F(abⅡ)2 antibody types.
Pharmaceutical composition containing the defined antibody
A pharmaceutical composition comprises the antibody molecule and optionally pharmaceutically acceptable diluents, carriers, vehicles, and/or excipients.
Overall, the claim set defines CTLA-4-binding antibodies by specific CDR SEQ ID NO combinations and narrows the molecules by additional sequence identity, antibody format, and binding specificity, including cross-species CTLA-4 binding and human CD28 non-binding. Dependent claims further require that the defined antibodies show improved depletion versus ipilimumab, supported by ADCC comparison and/or PBMC-NOG/SCID/FACS depletion readouts.
Stated Advantages
Improved depleting effect on Tregs (CTLA-4+FOXP3+) compared with ipilimumab.
Blocking of CTLA-4–B7.1 and CTLA-4–B7.2 while avoiding CD28 cross-reactivity.
Improved depleting effect on CTLA-4 positive cells, CD4 positive cells and/or Tregs compared with ipilimumab.
A defined binding specificity profile for one or more of human CTLA-4, cynomolgus monkey CTLA-4, and murine CTLA-4, and/or non-binding to human CD28.
Documented Applications
Depletion of CTLA-4 positive cells, CD4 positive cells, and/or Tregs assessed by in vitro ADCC and in vivo PBMC-NOG/SCID models with FACS quantification.
Use of the anti-CTLA-4 antibody in oncolytic vaccinia expressing the antibody and optionally GM-CSF as described in the document.
Tumor-local expression and replication characterization in experimental tumor models, including tumor-selective replication with evaluation of expression and antitumor activity and immune memory upon CT26 rechallenge.
Pharmacokinetic or kinetics assessment after intratumoral injection in tumor model systems including LoVo and CT26.
Antitumor activity and survival benefits using murine surrogate viruses with or without anti-PD1, including tumor growth inhibition or regression and immune memory upon rechallenge.
Interested in licensing this patent?