Aberrant cell-restricted immunoglobulins provided with a toxic moiety

Abstract

Described are immunoglobulins provided with a toxic moiety, comprising at least an immunoglobulin variable region that specifically binds to an MHC-peptide complex preferentially associated with aberrant cells. These immunoglobulins provided with a toxic moiety are preferably used in selectively modulating biological processes. The provided immunoglobulins provided with a toxic moiety are of particular use in pharmaceutical compositions for the treatment of diseases related to cellular aberrancies, such as cancers and autoimmune diseases.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a continuation of U.S. patent application Ser. No. 13 / 739,974, filed Jan. 11, 2013, pending, which application claims the benefit under 35 U.S.C. §119(e) to U.S. Ser. No. 61 / 586,568, filed on Jan. 12, 2012, the disclosure of each of which is hereby incorporated herein in its entirety by this reference.TECHNICAL FIELD[0002]The disclosure relates to the field of biotechnology and biotherapeutics. More specifically, it relates to immunoglobulins provided with a toxic moiety and human antibodies. It also relates to the use of these biotherapeutics in the treatment of a host suffering from a disease associated with aberrant cells, such as cancers and autoimmune diseases.BACKGROUND[0003]The development of immunoglobulin-drug conjugates is a drug development field that receives great attention nowadays. Humanized or human antibodies are the largest and most important class of immunoglobulins under investigation for use in anti...

AI Technical Summary

Benefits of technology

The patent describes a method for creating immunoglobulin-drug conjugates that can specifically target toxic cells while leaving healthy cells unharmed. The immunoglobulins used in the conjugates have specific binding domains that target specific peptides associated with aberrant cells. The toxic effect of the drug is chemically linked to the immunoglobulin, allowing for the toxic moiety to be attached without interfering with the immunoglobulin's function. The use of protein fusions and flexible linkers between the immunoglobulin and the toxic moiety further enhances the specificity and selectivity of the immunoglobulin-drug conjugates. Overall, this technology provides a targeted approach for treating cancer and tumors with reduced harmful side effects on healthy cells.

Problems solved by technology

Many of the conjugates have a limited degree of efficacy.

For example, the maximum tolerated dose of immunotoxins is relatively low due to their toxicity towards healthy tissue.

Lowering the dose, however, hampers the delivery of an efficacious amount of conjugate at the site of for example a tumor.

Thus, insufficient specificity for aberrant cells over healthy cells hampers desired efficacy and hampers obtaining the desired safety profiles of the nowadays immunoglobulin-drug conjugates.

Insufficient tumor cell specificity however still limited the therapeutic usefulness.

Even when selecting tumor cell surface antigens that are (highly) over-expressed at aberrant cells, still the low expression levels at healthy cells gives rise to insufficient selectivity of the antibody-drug conjugates.

Antibiotic calicheamicin conjugated to an anti-human CD33 monoclonal antibody was approved and used in the clinic, but was withdrawn due to serious side effects.

All these immunoglobulin-drug conjugate development programs thus inherently bear the risk for unacceptable safety profiles and consequent poor efficacy due to low maximum tolerated doses.

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