Therapeutic Mechanism and Efficacy of the Antibody–Drug Conjugate BAY 79-4620 Targeting Human Carbonic Anhydrase 9

Abstract

Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein that is expressed in many different tumors and yet restricted in normal tissues to the gastrointestinal tract. It is upregulated by hypoxia and correlates with tumor grade and poor survival in several tumor indications. Monoclonal antibodies (mAb) with single digit nanomolar binding affinity for CAIX were derived by panning with the recombinant ectodomain of CAIX against the MorphoSys HUCAL Gold library of human Fabs. Highest affinity Fabs were converted to full-length IgGs and subjected to further characterization based upon their avidity and selectivity for CAIX, their capacity to undergo internalization in CAIX-expressing cell lines, and their selective localization to CAIX-positive human xenografted tumors when administered to mice as fluorescent conjugates. Through this selection process, the 3ee9 mAb was identified, which upon conjugation to monomethyl auristatin E through a self-immolative enzyme-cleavable linker yielded the potent and selective CAIX antibody-drug conjugate CAIX-ADC (BAY 79-4620). In preclinical human xenograft models in mice representing several tumor indications, BAY 79-4620 showed potent antitumor efficacy and in some models showed partial and complete tumor shrinkage even following a single dose. The mechanism of action was shown by histology to involve the sequelae of events typical of antitubulin agents. Efficacy in murine preclinical models correlated semiquantitatively, with CAIX expression levels as determined by immunohistochemistry and ELISA. These preclinical data collectively support the development of BAY 79-4620 for the treatment of cancer patients with CAIX overexpressing tumors. Mol Cancer Ther; 11(2); 340-9. Ó2011 AACR.

Carbonic Anhydrase IX: From Biology to Therapy

“…Moreover, a human 3ee9 monoclonal antibody conjugated to monomethyl auristatin E through a self-cleavable linker showed potent antitumor efficacy in human xenograft models inducing partial-to-complete tumor shrinkage even following a single dose depending on the CA IX expression levels (Petrul et al 2012). These preclinical data support the development of the described antibodies for the treatment of cancer patients with CA IX overexpressing tumors.…”

Preclinical Antitumor Efficacy of BAY 1129980—a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody–Drug Conjugate for the Treatment of Non–Small Cell Lung Cancer

“…The marked in vivo efficacy of C4.4A-ADC was demonstrated in CDX and PDX models with homo-and heterogeneous C4.4A expression patterns to optimally mimic the situation in the clinic and using doses and schedules earlier shown to be efficient even in less sensitive models (37,38). C4.4A-ADC was particularly potent in two medium to high C4.4A-expressing NSCLC xenograft models, NCI-H292 and NCI-H322, resulting in equal or superior efficacy compared to SOC compounds.…”

Targeting carbonic anhydrase IX with small organic ligands

“…Scientists at Bayer attached the potent cytotoxic drug monomethyl auristatin E (MMAE) to the surface of a different anti-CAIX antibody (i.e., synthesized an antibody-drug conjugate) to deliver the drug into CAIX-expressing xenograft tumors [41 ]. The conjugate showed potent activity against strongly CAIX-positive tumors but showed little or no activity in tumors with low antigen expression.…”