Search

CN-122003249-A - Methods and compositions for non-PEG bioconjugates with ultra-high drug to agent ratios

CN122003249ACN 122003249 ACN122003249 ACN 122003249ACN-122003249-A

Abstract

The present invention provides novel non-PEG polymer bioconjugates having ultra-high drug to agent ratios that bind to cancer-associated antigens. non-PEG polymer bioconjugates with ultra-high DAR conjugated to cancer-associated antigens can deliver at least one drug to cancer cells. Methods of using the bioconjugates, such as methods of inhibiting tumor growth, and methods of making the bioconjugates are also provided.

Inventors

  • Anthony. Roman Simakov
  • Krzysztof Matthias Shevsky
  • Laura. Benjamin
  • ADAM WALKER
  • Andrew Cassik
  • Amanda Mingxi
  • Matthew Cummins
  • Cassandra Cliff Field
  • DAVID WILSON

Assignees

  • 迈瑞斯治疗公司

Dates

Publication Date
20260508
Application Date
20240925
Priority Date
20230925

Claims (20)

  1. 1. A bioconjugate comprising an agent linked to a non-polyethylene glycol (PEG) polymer, wherein the non-PEG polymer is coupled to a first drug and the agent binds to a cancer-associated antigen, and wherein the bioconjugate has a drug to agent ratio (DAR) of at least 100:1.
  2. 2. A method of preparing the bioconjugate of claim 1, comprising: (a) A non-PEG polymer backbone comprising Chain Transfer Agent (CTA) and one or more monomer units is prepared by reversible addition fragmentation chain transfer (RAFT) polymerization, Wherein at least one monomer unit comprises an initiator molecule for Atom Transfer Radical Polymerization (ATRP); (b) Preparing a non-PEG polymer comprising the non-PEG polymer backbone of (a) and one or more monomer units by ATRP, Wherein at least one monomer unit comprises a functional group capable of click reaction; (c) Coupling a first drug to said non-PEG polymer of (b) via a click-reaction capable functional group, and (D) Coupling an agent that binds a cancer-associated antigen to the non-PEG polymer of (c).
  3. 3. A method of preparing the bioconjugate of claim 1, comprising: (a) Preparing a non-PEG polymer backbone comprising Chain Transfer Agent (CTA) molecules and one or more monomer units by reversible addition fragmentation chain transfer (RAFT) polymerization; wherein at least one monomer unit comprises an initiator molecule for Atom Transfer Radical Polymerization (ATRP); (b) Coupling an agent that binds a cancer-associated antigen to the non-PEG polymer backbone of (a); (c) Preparing a non-PEG polymer comprising the non-PEG polymer backbone of (b) and one or more monomer units by ATRP, Wherein at least one monomer unit comprises a functional group capable of undergoing a click reaction, and (D) Coupling a first drug to the non-PEG polymer of (c) through the functional group capable of click reaction.
  4. 4. The bioconjugate of any one of claims 1-3, wherein the DAR is at least 110:1.
  5. 5. The bioconjugate of any one of claims 1-4, wherein the DAR is at least 120:1.
  6. 6. The bioconjugate of any one of claims 1-5, wherein the DAR is at least 130:1.
  7. 7. The bioconjugate of any one of claims 1-6, wherein the DAR is at least 140:1.
  8. 8. The bioconjugate of any one of claims 1-7, wherein the DAR is at least 150:1.
  9. 9. The bioconjugate of any one of claims 1-8, wherein the DAR is at least 160:1.
  10. 10. The bioconjugate of any one of claims 1-9, wherein the DAR is at least 170:1.
  11. 11. The bioconjugate of any one of claims 1-10, wherein the DAR is at least 180:1.
  12. 12. The bioconjugate of any one of claims 1-11, wherein the DAR is at least 190:1.
  13. 13. The bioconjugate of any one of claims 1-12, wherein the DAR is at least 200:1.
  14. 14. The bioconjugate of any one of claims 1-13, wherein the DAR is at least 210:1.
  15. 15. The bioconjugate of any one of claims 1-14, wherein the DAR is at least 220:1.
  16. 16. The bioconjugate of any one of claims 1-15, wherein the DAR is at least 230:1.
  17. 17. The bioconjugate of any one of claims 1-16, wherein the DAR is at least 240:1.
  18. 18. The bioconjugate of any one of claims 1-17, wherein the DAR is at least 250:1.
  19. 19. The bioconjugate of any one of claims 1-18, wherein the DAR is at least 260:1.
  20. 20. The bioconjugate of any one of claims 1-19, wherein the DAR is at least 270:1.

Description

Methods and compositions for non-PEG bioconjugates with ultra-high drug to agent ratios Cross Reference to Related Applications The present application claims priority from U.S. provisional application No. 63/540,322, filed on 25 at 9 at 2023, U.S. provisional application No. 63/557,410, filed on 23 at 2 at 2024, and U.S. provisional application No. 63/666,550, filed on 1 at 7 at 2024, the contents of which are incorporated herein by reference in their entirety. Reference is made to the electronically submitted sequence listing The contents of the list of sequences submitted electronically (name: 5423_003PC03_Sequence listing_ST26. Xml; size: 37168 bytes; date of creation: 2024, 9, 25 days) are incorporated herein by reference in their entirety. Technical Field The field of the invention generally relates to bioconjugates comprising agents (e.g., antibodies, antigen-binding fragments thereof, cytokines, enzymes, or polynucleotides) that bind to cancer-associated antigens, the cancer-associated antigens are linked to non-polyethylene glycol (PEG) polymers with drugs (e.g., chemotherapeutic drugs), methods of treating cancer using the bioconjugates, and/or methods of making the bioconjugates. Background Cancer is one of the leading causes of death in developed countries, with more than one million people diagnosed with cancer each year and 500,000 deaths in the united states alone. In general, it is estimated that more than one-third of people will develop some form of cancer throughout life. There are 200 different types of Cancer, four of which-breast, lung, colorectal and prostate Cancer-account for more than half of all new cases (Jemal et al, 2003, cancer j. Clin. 53:5-26). Bioconjugates and antibody-drug conjugates ("ADCs") provide a class of potent anticancer agents that are effective against a range of cancers. Approved ADCs are typically composed of three distinct components, a reagent (e.g., an antibody), a linker, and a cytotoxic moiety (e.g., a taxane). Antibodies or other agents that specifically bind to cancer surface antigens are used to deliver cytotoxic drugs in the form of bioconjugates. The number of drug molecules conjugated per antibody in an ADC is typically distributed over a range of between 0 and 8 per antibody. There is a need to develop new ADCs and bioconjugates with higher drug to agent ratios (DARs). Disclosure of Invention The present invention provides bioconjugates having ultra-high DAR comprising antibodies, antigen-binding fragments thereof, or other targeting agents (e.g., cytokines, enzymes, polynucleotides), which bind to cancer-associated antigens and are conjugated to one or more drugs or more drug types, and methods of use thereof. Compositions (e.g., pharmaceutical compositions) comprising bioconjugates are also provided. In addition, methods of making and using the bioconjugates, such as methods of using the bioconjugates to inhibit tumor growth and/or to treat cancer, are also provided. Thus, in one aspect, the invention provides a bioconjugate comprising an agent linked to a non-polyethylene glycol (PEG) polymer, wherein the non-PEG polymer is coupled to a first drug, the agent binds to a cancer-associated antigen, and wherein the bioconjugate has a drug to agent ratio (DAR) of at least 20:1. In another aspect, the invention provides a bioconjugate comprising an agent linked to a non-polyethylene glycol (PEG) polymer, wherein the non-PEG polymer is coupled to a first drug and the agent binds to a cancer-associated antigen, and wherein the bioconjugate has a drug to agent ratio (DAR) of at least 100:1. In some aspects, the present disclosure provides a method of preparing a bioconjugate comprising: (a) A non-PEG polymer backbone comprising Chain Transfer Agent (CTA) and one or more monomer units is prepared by reversible addition fragmentation chain transfer (RAFT) polymerization, Wherein at least one monomer unit comprises an initiator molecule for Atom Transfer Radical Polymerization (ATRP); (b) Preparing a non-PEG polymer comprising the non-PEG polymer backbone of (a) and one or more monomer units by ATRP, Wherein at least one monomer unit comprises a functional group capable of click reaction; (c) Coupling the first drug to the non-PEG polymer of (b) via a click-reaction-capable functional group, and (D) Coupling an agent that binds a cancer-associated antigen to the non-PEG polymer of (c). In some aspects, the invention provides a method of preparing a bioconjugate comprising: (a) Preparing a non-PEG polymer backbone comprising Chain Transfer Agent (CTA) molecules and one or more monomer units by reversible addition fragmentation chain transfer (RAFT) polymerization; wherein at least one monomer unit comprises an initiator molecule for Atom Transfer Radical Polymerization (ATRP); (b) Coupling an agent that binds a cancer-associated antigen to the non-PEG polymer backbone of (a); (c) Preparing a non-PEG polymer comprising the non-PEG polymer backbone of (b) and