Optimized Anti-CD3 Bispecific Antibodies and Uses Thereof

Abstract

The present invention provides antibodies that bind to CD3 with weak or no detectable binding affinity and methods of using the same. According to certain embodiments, the antibodies of the invention bind human CD3 with low affinity and induce human T cell proliferation and hence induce T cell-mediated killing of tumor cells with high efficacy. According to certain embodiments, the present invention provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human CD3 with weak or no detectable binding affinity in an in vitro assay, and a second antigen-binding molecule that specifically binds human tumor-associated antigen. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of tumors expressing target antigen, such as PSMA. The antibodies and bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced targeted immune response is desired and / or therapeutically beneficial. For example, the antibodies of the invention are useful for the treatment of various cancers or other diseases where immunotherapy, i.e. effector cell immunomodulation is warranted.

Description

REFERENCE TO A SEQUENCE LISTING[0001]This application incorporates by reference the Sequence Listing submitted in Computer Readable Form as file 10151WO01_ST25.txt, created on Sep. 22, 2016 and containing 264,418 bytes.FIELD OF THE INVENTION[0002]The invention related to bispecific antibodies, targeting an effector antigen, such as CD3 antigen, and a tumor associated antigen, and methods of tumor killing. The invention relates to methods of reducing or eliminating tumor burden and controlling the toxic side effects that may be associated with tumor immunotherapy. The present invention provides bispecific antibodies comprising an effector arm which binds to an effector antigen with weak affinity or with no detectable binding affinity, for example, an anti-CD3 antigen-binding arm which binds to CD3 with a KD of greater than about 500 nM, in an in vitro affinity binding assay.BACKGROUND[0003]The promise of therapeutic bispecific antibodies (bsAbs), particularly in cancer immunotherapie...

AI Technical Summary

Benefits of technology

The patented bonpecific antibodies can fight tumors in animals with low amounts of CD3 antigen. They can also work in animals with compromised immune systems.

Problems solved by technology

Differential outcomes are difficult to predict depending on the T cell subset being triggered to respond, as well as the state of the T cell being stimulated.

It is well-known that bsAbs do not give consistent results (Manzke O, et al.

Certain bispecific therapies have been successful, yet, as with many cancer therapies, it comes with a price.

Toxicity is the leading cause of failure among cancer therapeutics.

It is well known that toxicity of so-called chemotherapeutic drugs is the leading cause of patient side effects and secondary maladies.

The act of “cell killing” itself is wrought with trouble for the patient.

However, methods of reducing binding affinity of antibody molecules to near or beyond the detectable level of binding have not been described, nor shown to have the requisite efficacy for tumor reduction or suppression.

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