Antibody Conjugate Therapeutics: Challenges and Potential

Abstract

Antibody conjugates are a diverse class of therapeutics consisting of a cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates is marked by hurdles that have been identified and overcome. Early conjugates used mouse antibodies; cytotoxic agents that were immunogenic (proteins), too toxic, or not sufficiently potent; and linkers that were not sufficiently stable in circulation. Investigators have explored 4 main avenues using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or antibody fragment-protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small-molecule drug conjugates, and antibody-enzyme conjugates administered along with small-molecule prodrugs that require metabolism by the conjugated enzyme to release the activated species. Only antibody-radionuclide conjugates and antibody-drug conjugates have reached the regulatory approval stage, and nearly 20 antibody conjugates are currently in clinical trials. The time may have come for this technology to become a major contributor to improving treatment for cancer patients.

Increasing the Antitumor Effect of an EpCAM-Targeting Fusion Toxin by Facile Click PEGylation

“…We previously reported on a fusion toxin composed of the high affinity anti-EpCAM DARPin Ec4 and domain I-truncated ETA (ETA 00 , also known as PE40), which could be expressed at very high yields and demonstrated promising antitumor effects (25). Fusion toxins of this rather small size, however, have very short elimination half-lives of hardly more than 10 minutes, which negatively affects tumor targeting (6). To increase the therapeutic index, the half-life must be extended without increasing systemic toxicity.…”

“…To generate a reversibly PEGylated fusion toxin as control, a 3C protease cleavage site was introduced between the N-terminal MRGSH 6 -tag and DARPin. This was encoded by insertion of a double-stranded oligonucleotide at a BamHI site.…”

“…Recent advances in antibody engineering and linker technology, together with a growing arsenal of potent anticancer agents, have paved the way for the development of drug conjugates targeting tumors with exquisite efficacy and specificity (1)(2)(3). In theory, many different types of payloads can be linked to antibodies; in practice, however, engineering ADC with high stability and efficacy has been hampered by technical limitations and unfavorable properties inherent to the antibody format (3)(4)(5)(6).…”

Milatuzumab–SN-38 Conjugates for the Treatment of CD74+ Cancers

“…ADCs have been of considerable research interest for many years, but only recently peaked, primarily due to the clinical success of 2 conjugates prepared with socalled "supertoxic" agents that have subnanomolar potency, which replaced many of the earlier ADCs prepared using chemotherapeutic agents that had potencies in the nanomolar levels (40)(41)(42)(43)(44)(45)(46). However, drug potency or even its specific mechanism of action is not the only defining property that affords optimal performance of an ADC.…”

Assessment of Solvated Interaction Energy Function for Ranking Antibody–Antigen Binding Affinities

“…4,5 Recent platforms to improve antibody efficacy and/or reduce side effects include bispecific antibodies and antibody−drug conjugates, both of which have great potential and currently enjoy tremendous interest. 6,7 Many of these platforms depend on antibodies obtained by animal immunization, e.g., via the hybridoma technique, 8 and often require subsequent optimization. 9,10 Humanization, required for most antibodies from animal sources, typically leads to a reduction in affinity.…”