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US-12624123-B2 - Compositions and methods for reducing off-target toxicity of antibody drug conjugates

US12624123B2US 12624123 B2US12624123 B2US 12624123B2US-12624123-B2

Abstract

Provided are compositions and methods for reducing off-target toxicity of antibody-drug conjugates (ADCs). The compositions comprise an ADC, and an agent targeted to the drug (payload) that is delivered by or derived from the ADC. The ADC and the agent targeted to the payload may be delivered together or separately in the treatment of various conditions (such as tumors) by ADCs. Examples of agents targeted to payload include antibodies, fragments, or modifications thereof.

Inventors

  • Joseph P. Balthasar
  • Brandon M. BORDEAU
  • Toan Duc NGUYEN
  • Joseph Ryan POLLI

Assignees

  • THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK

Dates

Publication Date
20260512
Application Date
20201204

Claims (11)

  1. 1 . A composition comprising an antigen binding antibody fragment and a pharmaceutical carrier, wherein the antigen binding fragment comprises the sequence of SEQ ID NO:3; or a heavy chain comprising the sequence of SEQ ID NO:4 and a light chain comprising the sequence of SEQ ID NO:5; or SEQ ID NO:6; or the sequence of SEQ ID NO:7; or the sequence of SEQ ID NO: 8; or the sequence of SEQ ID NO:9; or the sequence of SEQ ID NO:10; or the sequence of SEQ ID NO: 11; or the sequence of SEQ ID NO:69.
  2. 2 . The composition of claim 1 , wherein the antigen binding antibody fragment comprises the sequence of SEQ ID NO:3.
  3. 3 . The composition of claim 1 , wherein the antigen binding antibody fragment comprises the heavy chain comprising the sequence of SEQ ID NO:4 and a light chain comprising the sequence of SEQ ID NO:5.
  4. 4 . The composition of claim 1 , wherein the antigen binding antibody fragment comprises the sequence of SEQ ID NO:6.
  5. 5 . The composition of claim 1 , wherein the antigen binding antibody fragment comprises the sequence of SEQ ID NO:7.
  6. 6 . The composition of claim 1 , wherein the antigen binding antibody fragment comprises the sequence of SEQ ID NO:8.
  7. 7 . The composition of claim 1 , wherein the antigen binding antibody fragment comprises the sequence of SEQ ID NO:9.
  8. 8 . The composition of claim 1 , wherein the antigen binding antibody fragment comprises the sequence of SEQ ID NO:10.
  9. 9 . The composition of claim 1 , wherein the antigen binding antibody fragment comprises the sequence of SEQ ID NO: 11.
  10. 10 . The composition of claim 1 , wherein the antigen binding antibody fragment comprises the sequence of SEQ ID NO:69.
  11. 11 . The composition of claim 1 , further comprising an antibody drug conjugate (ADC) wherein the drug comprised by the ADC is a derivative of camptothecin.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional patent application No. 62/943,358, filed on Dec. 4, 2019, the disclosure of which is incorporated herein by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in txt format and is hereby incorporated by reference in its entirety. Said txt copy was created on Dec. 4, 2020, is named “011520_01569_ST25.txt” and is 82,000 bytes in size. BACKGROUND OF THE DISCLOSURE Anti-cancer antibody-drug conjugates (ADCs) are being employed for targeted delivery of drugs, which may be toxins or other cell growth inhibitors (termed here as drug or payload molecules) to cancer cells. Nine ADCs are currently marketed in the US, and approximately 100 ADCs are in development (Chau et al., Lancet. 2019; 394(10200):793-804; Coats et al., Clin Cancer Res. 2019. Epub Apr. 14, 2019. doi: 10.1158/1078-0432.CCR-19-0272; Wolska-Washer et al., Drug Saf. 2019; 42(2):295-314; Beck et al., Nat Rev Drug Discov. 2017; 16(5):315-37). However, clinical application of ADCs has been somewhat disappointing; many ADCs have failed in clinical trials as a result of substantial off-target toxicity, which has limited tolerable doses below levels needed for tumor eradication (Coats et al., Clin Cancer Res. 2019. Epub Apr. 14, 2019. doi: 10.1158/1078-0432.CCR-19-0272; Kim et al., Biomol Ther (Seoul). 2015; 23(6):493-509; de Goeij et al., Curr Opin Immunol. 2016; 40:14-23; Khera et al., BioDrugs. 2018; 32(5):465-80). As a result of associated toxicity to non-target sites, the early promise of ADCs is not fully realized and therefore, there is an ongoing need in the area of cancer therapy to develop new approaches to minimize non-target toxicity of therapeutic payload drug molecules without compromising their anti-tumor efficacy. SUMMARY OF THE DISCLOSURE This disclosure provides compositions and methods for reducing off-target toxicity of ADCs. For example, the present compositions and methods can be used for treatment of tumors with ADCs, while reducing off-target toxicity of the ADCs. The drug in the ADC may be referred to herein as “payload”. The compositions comprise an ADC and an agent targeted to the payload that is delivered by or derived from the ADC. The agent targeted to the payload is termed herein as “payload-binding agent” or PBA. The ADC and the payload-binding agent may be provided in the same composition or in different compositions. The payload binding agent may be a peptide or an antibody or a fragment or an antibody mimetic or a modification thereof directed to the ADC payload, and which binds to the payload. If the payload binding agent is an antibody or a fragment or modification thereof, it may be referred to as “anti-payload antibody”. In an aspect, this disclosure provides a method for inhibiting or preventing the growth of one or more tumors comprising administering to an individual in need of treatment, an ADC and a payload binding agent, wherein the payload binding agent has specific affinity for the ADC payload. The ADC and the payload binding agent may be administered in the same composition or different compositions, via the same routes or via different routes, or using the same regimen or different regimen. In an aspect, this disclosure provides peptides or antibodies or antibody fragments or modifications, which are specific for an ADC payload molecule. The anti-payload antibody may be whole immunoglobulin molecules such as polyclonal or monoclonal antibodies or chimeric antibodies including humanized antibodies. The antibody fragments or modification can be antigen-binding fragments thereof, including, but not limited to, Fab, F(ab′), F(ab′)2, Fv, dAb, Fd, CDR fragments, single-chain antibodies (scFv), bivalent single-chain antibodies, single-chain phage antibodies, diabodies, or single domain antibodies (nanobodies) and the like. Antibody mimetics may include affibodies, nanofitins, or the like. The fragments of the antibodies may be produced synthetically or by enzymatic or chemical cleavage of intact immunoglobulins or may be genetically engineered by recombinant DNA techniques. These techniques are well known in the art. The antibody or fragments or modifications thereof may be modified so as to impart longer half-life, stability and the like. In an embodiment, the disclosure provides antibodies or fragments or derivatives thereof directed to several ADC payload, including full length antibodies, scFv, Fab and other fragments directed specifically to maytansinoids, auristatins, camptothecins, pyrrolobenzdiazepines, and calicheamicin. BRIEF DESCRIPTION OF THE FIGURES FIG. 1. Chemical reaction schematics for developing immunogen conjugates. A) MMAF was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in MES buffer, pH 4.2 with carrier proteins keyhole limpet hemocyanin (KLH) or bovine serum albumin (BSA). The reaction favors the carboxylic