Improving the Therapeutic Index in Cancer Therapy by Using Antibody–Drug Conjugates Designed with a Moderately Cytotoxic Drug

Abstract

The antibody-drug conjugate (ADC), IMMU-130, of the moderately cytotoxic topoisomerase I inhibitor, SN-38, and the CEACAM5-targeted humanized antibody (mAb), labetuzumab, was evaluated in model systems of human colon carcinoma and in phase I clinical trials of heavily pretreated patients with metastatic colorectal cancer. The conjugate, designed with a near-homogeneous drug substitution of 7-8 SN-38/mAb and with a linker that released 50% of the drug in ∼20 h, showed significant antitumor effects compared to a nontargeted ADC in human tumor xenografts, which could be augmented in combination with bevacizumab. The advantage of fractionated dosing was demonstrated, with potential implications for the clinical dosing schedule. Biodistribution comparing IMMU-130 with labetuzumab showed that the conjugate cleared somewhat faster from the blood, but this did not affect tumor uptake and retention. The use of an ultrastable linker in the conjugate design abrogated antitumor effects. A tolerability study in rabbits showed a high safety margin, with no-observed-adverse-effect level (NOAEL) corresponding to a cumulative human-equivalent protein dose of 40-60 mg/kg. The preclinical findings appear to be corroborated in two phase I clinical trials, with high tolerability and evidence of antitumor activity, including objective responses. The impact of the ADC design on the utility of IMMU-130, tailored to a poorly internalizing target, is discussed.

IMMU-140, a Novel SN-38 Antibody–Drug Conjugate Targeting HLA-DR, Mediates Dual Cytotoxic Effects in Hematologic Cancers and Malignant Melanoma

“…Likewise, in A-375 melanoma, there were no changes in p-ERK levels mediated by either IMMU-114 or IMMU-140. This is consistent with reports that in solid tumors, including melanoma, HLA-DR signaling is through phosphorylation of p125 focal adhesion kinase and not ERK (2,30). In AML, it has been suggested that increased expression of Bcl-2 proteins, in particular Mcl-1, act to attenuate apoptosis (35,36).…”

“…The moderately stable linker in these unconventional ADCs enables the drug to be released in the acidic pH of tumor microenvironment, while internalization further increases the drug's bioavailability. These design features, while not amenable to showing specificity in vitro, have resulted in encouraging clinical activity of other ADCs (anti-Trop-2 ADC, anti-CEACAM5 ADC) in solid cancer therapies (14)(15)(16)(17)30). In particular, the same conjugation method has been used to create an anti-Trop-2 SN-38-ADC (sacituzumab govitecan, IMMU-132) that targets Trop-2 on solid tumors, and likewise has been shown to be superior to parental antibody both in vitro and in vivo (18,19,31).…”

Emerging formats for next-generation antibody drug conjugates

“…Payload internalization was seen but no cytotoxicity data was disclosed. A similar 'bispecific/bifunctional capture idea is Immunomedics' Dock and Lock approach, which is based on the non-covalent interaction between the regulatory subunit of cAMP-dependent protein kinase (dimerization and docking domain) and a kinase anchor domain (AD), which assembles into a covalently locked complex [75].…”

Identification of initial leads directed at the calmodulin-binding region on the Src-SH2 domain that exhibit anti-proliferation activity against pancreatic cancer

“…All these results indicate, not surprisingly, that these initial leads in Table-1 are far from optimal, and are potential candidates for further development by structure-guided design and chemical synthesis. Since some of these initial leads exhibit varying degrees of cytotoxicity against the normal cells that we tested against (i.e., MCF10A), they and their derivatives are also excellent candidates for targeted delivery by antibody-conjugation 33 or nanoparticles 34 to deliver the inhibitors to pancreatic cancer cells with high specificity and with minimal effects on normal cells.…”