Addressing the Immunogenicity of the Cargo and of the Targeting Antibodies with a Focus on Deimmunized Bacterial Toxins and on Antibody-Targeted Human Effector Proteins

Abstract

Third-generation immunotoxins are composed of a human, or humanized, targeting moiety, usually a monoclonal antibody or an antibody fragment, and a non-human effector molecule. Due to the non-human origin of the cytotoxic domain, these molecules stimulate potent anti-drug immune responses, which limit treatment options. Efforts are made to deimmunize such immunotoxins or to combine treatment with immunosuppression. An alternative approach is using the so-called “human cytotoxic fusion proteins”, in which antibodies are used to target human effector proteins. Here, we present three relevant approaches for reducing the immunogenicity of antibody-targeted protein therapeutics: (1) reducing the immunogenicity of the bacterial toxin, (2) fusing human cytokines to antibodies to generate immunocytokines and (3) addressing the immunogenicity of the targeting antibodies.

Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin

“…These findings were associated with absence of any detectable systemic (not shown) or histological toxicity in off‐target organs during the experiment time (Figure ). It could not be fully excluded that in longer treatments ricin (as well as other recombinant toxins or therapeutic fusion proteins) may induce an immune response, that if involving antigens shared with endogenous protein might lead to adverse effects . However, the modified version of ricin used here avoids the vascular leak syndrome (VLS), the major concern in the clinical trial of a ricin A‐antibody (CD19/CD12) immunotoxin (https://clinicaltrials.gov/ct2/show/NCT01408160).…”

“…This could be done by an approach similar to that carried out for diphtheria and P. aeruginosa toxins. These microbial proteins, components of most of third generation immunotoxins under clinical evaluation, are successfully engineered by the removal of nonessential sequences and by the genetic elimination of antigenic T and B cell epitopes, without compromising their antitumor activity …”

Critical Issues in the Development of Immunotoxins for Anticancer Therapy

“…The clinical development of ITs has been frequently impeded by the induction of immune responses, and this property is known as immunogenicity. 72,73 Particularly, ITs carrying heterogeneous bacteria-and plant-derived toxins are highly immunogenic and raise T-celledependent and B-cellemediated anti-drug antibodies (ADAs) against the foreign toxin moiety in patients with a healthy immune system. 46,73 ADAs can neutralize the IT, thereby causing it to lose its efficacy, and accelerate its clearance from the body as well as cause serious immune systemerelated adverse effects preventing long-term or repeated administration in clinical trials.…”

“…71,90 Aside from the heterologous toxin moiety, the antibody-based targeting moiety could be immunogenic, 86 especially a moiety based on murine and chimeric antibodies used in the firstand second-generation ITs. 72 To address this problem, humanized and fully human antibodies are utilized in a recent version of ITs. 88 Another potential solution preventing immunogenicity is administration of ITs via a cellular delivery system.…”

Immunotoxin Screening System: A Rapid and Direct Approach to Obtain Functional Antibodies with Internalization Capacities

“…For future generation of ITs with enhanced efficacies and reduced adverse events, improved target recognition and reduced immunogenicity are key factors. The latter topic, which focuses on immunogenicities associated with antibodies, and especially bacterial and plant toxins are reviewed elsewhere [ 35 , 36 , 37 ] and beyond the scope of this review article. Improvement on target recognition is dependent upon specificity and affinity of monoclonal antibody.…”