Patients being treated for cancer may often benefit from a combination of systemic cancer chemotherapies. The rationale for the combination of multiple anti-cancer therapies is that drugs that work by different mechanisms may be more effective since they may decrease or slow the likelihood of resistance. Furthermore, when treatment regimens with drugs with different mechanisms of action are combined, each drug may be used at its optimal dose, with limited or no intolerable adverse effects. This, in turn, may improve treatment outcomes.
Today, all approved and commercially available antibody-drug conjugates (ADCs), drugs combining the high target specificity of antibodies together with strong antitumoral properties provided by the attached cytotoxic agent, contain single-drug payloads. And while the targeted approach of an ADC typically yields favorable results, (acquired) drug resistance often emerges, limiting the effectiveness of these therapies. [1][2] Scientists have tried to understand the development of resistance to ADCs, which may include down-regulation of the target antigen and up-regulation of drug efflux pumps [3][4]
However, considering the benefits of combination chemotherapies, combining ADCs with different drugs or using ADCs with multiple-drug payloads may circumvent the development of ADC-associated drug resistance. Rather than combining two separate ADCs with different payloads, scientists have rationalized that a dual-drug ADC, an ADC with two different payloads combining, multiple, distinct mechanisms of action, would potentially be achieved by the co-delivery of two different payloads conjugated to the same antibody at equimolar concentrations.
Next-generation ADCs
With the emergence of resistance to current ADC therapeutics, arming a single antibody with two different cytotoxic payloads may provide an attractive option in the development of next-generation ADCs.
To demonstrate the possible benefits of ADCs with dual drug delivery, Levengood et al., in 2017, prepared an ADCs containing two different tubulin polymerization inhibitors. The group linked two auristatin drug-linkers (monomethyl auristatin E and monomethyl auristatin F) each with differing physiochemical properties, exerting complementary anti-cancer activities, on an anti-CD30 antibody. This work clearly demonstrated a possible effective approach for the construction of potent dual-drug ADCs and how the delivery of multiple cytotoxic payloads may lead to improved ADC activities.[5]
Later, Kumar et al. reported on the development of a heterotrifunctional linker to generate a dual-drug ADC with MMAE and a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer payload, [6] while Nilchan et al. employed dual antibody conjugation to link a HER2-targeting antibody via site-specific conjugation at engineered selenocysteine and cysteine residues (engineered thio-selenomab) to generate a dual-drug ADC combining the tubulin-targeting payload MMAF and the DNA topoisomerase II inhibitor PNU-159682, a highly potent metabolite of the anthracycline nemorubicin. These dual-drug ADCs did, however, not simultaneously act on two different targets. [7]
TRIObody Drug Conjugates
Among the companies researching the therapeutic possibility of the next generation ADCs and advancing the development of dual-action/dual-drug ADCs, is Trio Pharmaceuticals, a privately-held cancer therapeutics company incubating at The California Institute for Quantitative Biosciences (QB3) at the University of California San Francisco in San Francisco, CA.
Trio has developed a novel cancer therapeutics called TRIObody Drug Conjugate™ or TDC™, a novel dual-action antibody-drug conjugate.
TRIObody Drug Conjugates are a first-in-class ADC with dual-functionality. This dual-action TDCs utilize targeted payloads delivery to stop both tumor growth and immunosuppression. By generating a less immunosuppressive tumor microenvironment, TDC enhances the activation of tumor-specific immune effector cells further facilitating cancer cell destruction.
Earlier this week Trio Pharmaceuticals and Ajinomoto Bio-Pharma Services, a biopharmaceutical contract development and manufacturing organization (CDMO), confirmed signing a collaborative agreement to evaluate Ajinomoto’s AJICAP™, a proprietary site-specific conjugation technology for the development of Trio’s TDCs.
The companies agreed to use Ajinomoto proprietary site-specific conjugation technology, which is compatible with varied antibody modalities, to conjugate a cytotoxic payload to Trio’s lead oncology candidate with Trio evaluating the functionality of their TDC.
Improving the efficacy of cancer immunotherapies
Commenting on the development of Trio Pharmaceutical’s TRIObody Drug Conjugate and the collaboration with Ajinomoto, Sandip Patel, M.D, Associate Professor, University of California San Diego and Deputy Director, San Diego Center for Precision Immunotherapy, who has a strong clinical practice and research in immunotherapy in cancer, remarked: “We are very interested in the development of Trio’s dual-action antibody-drug conjugate, TDC™, and the success of this collaboration.”
“My group is currently researching ways to eliminate tumors from the body post-immune checkpoint inhibitor treatment by stimulating a patient’s immune system. I am interested in applying Trio’s drug in clinical settings to understand if it activates a patient’s immune system to launch an immune attack on the tumor. We have conducted multiple first in human immunotherapy clinical trials and have a patient population that may benefit from Trio’s approach,” Patel added.
Trio’s dual-action TDC™ will improve the efficacy of current cancer immunotherapies, such as immune checkpoint inhibitors, both as an adjuvant and neo-adjuvant treatment,” he concluded.
Advantage
According to the developers, the advantage of Ajinomoto’s proprietary technology is its “off-the-shelf” feature, allowing any antibody-drug at any stage of development to be conjugated to drug-payloads of choice without the need to modify the sequence. In contrast to traditional Cys-maleimide and Lys-succinimide conjugation technologies, using this conjugation generates ADCs with high yields.
“We are very excited to collaborate with Aji Bio-Pharma to develop our proprietary dual-action TDC,” noted Shiva Bhowmik, Ph.D, Founder and Chief Executive Officer of Trio Pharmaceuticals.
“[I believe that] Ajinomoto’s conjugation technology [may] mark a new beginning in the ADC field, allowing the generation of ADCs with site-specific conjugation without a change in antibody sequence, a rate-limiting step in the development of site-specific ADCs. Setting an early collaboration with Aji Bio-Pharma will ease our cGMP plans for clinical development,” Bhowmik added.
“[Our technology] was developed to create novel ADCs with therapeutic window enhancements while shortening the development timeline. We are excited to collaborate with TRIO as they advance TDC technology, developing a new class of ADCs. This collaboration marks a new avenue of development in the ADC field,” noted Brian Mendelsohn, BSc, Ph.D., Director, Process Development and Technology Transfer at Aji Bio-Pharma.
“We are very excited to collaborate with Trio in the development of dual-action ADCs. [With…] a talented and dedicated team of ADC scientists and strong CMC capabilities, [we] will benefit Trio’s development of this novel ADC,” concluded Tatsuya Okuzumi, Ph.D., Associate General Manager, Business Development, Ajinomoto.
Reference
[1] Loganzo F, Tan X, Sung M, et al. Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther. 2015;14(4):952‐963. doi:10.1158/1535-7163.MCT-14-0862
[2] Chen R, Hou J, Newman E, et al. CD30 Downregulation, MMAE Resistance, and MDR1 Upregulation Are All Associated with Resistance to Brentuximab Vedotin. Mol Cancer Ther. 2015;14(6):1376‐1384. doi:10.1158/1535-7163.MCT-15-0036
[3] García-Alonso S, Ocaña A, Pandiella A. Resistance to Antibody-Drug Conjugates. Cancer Res. 2018;78(9):2159‐2165. doi:10.1158/0008-5472.CAN-17-3671
[4] Loganzo F, Sung M, Gerber HP. Mechanisms of Resistance to Antibody-Drug Conjugates. Mol Cancer Ther. 2016;15(12):2825‐2834. doi:10.1158/1535-7163.MCT-16-0408
[5] Levengood MR, Zhang X, Hunter JH, et al. Orthogonal Cysteine Protection Enables Homogeneous Multi-Drug Antibody-Drug Conjugates. Angew Chem Int Ed Engl. 2017;56(3):733‐737. doi:10.1002/anie.201608292
[6] Kumar A, Kinneer K, Masterson L, et al. Synthesis of a heterotrifunctional linker for the site-specific preparation of antibody-drug conjugates with two distinct warheads. Bioorg Med Chem Lett. 2018;28(23-24):3617‐3621. doi:10.1016/j.bmcl.2018.10.043
[7] Li X, Patterson JT, Sarkar M, et al. Site-Specific Dual Antibody Conjugation via Engineered Cysteine and Selenocysteine Residues. Bioconjug Chem. 2015;26(11):2243‐2248. doi:10.1021/acs.bioconjchem.5b00244
