Safety Of Antibody-drug Conjugates Research Articles

A comparison of the activity, lysosomal stability, and efficacy of legumain-cleavable and cathepsin-cleavable ADC linkers

Over the past two decades, antibody-drug conjugates (ADCs) have emerged as a highly effective drug delivery technology. ADCs utilise a monoclonal antibody, a chemical linker, and a therapeutic payload to selectively deliver highly potent pharmaceutical agents to specific cell types. Challenges such as premature linker cleavage and clearance due to linker hydrophobicity have adversely impacted the stability and safety of ADCs. While there are various solutions to these challenges, our team has focused on replacement of hydrophobic ValCit linkers (cleaved by CatB) with Asn-containing linkers that are cleaved by lysosomal legumain. Legumain is abundantly present in lysosomes and is known to play a role in tumour microenvironment dynamics. Herein, we directly compare the lysosomal cleavage, cytotoxicity, plasma stability, and efficacy of a traditional cathepsin-cleavable ADC to a matched Asn-containing legumain-cleavable ADC. We demonstrate that Asn-containing linker sequences are specifically cleaved by lysosomal legumain and that Asn-linked MMAE ADCs are broadly active against a variety of tumours, even those with low legumain expression. Finally, we show that AsnAsn-linked ADCs exhibit comparable or improved efficacy to traditional ValCit-linked ADCs. Our study paves the way for replacement of the traditional ValCit linker technology with more hydrophilic Asn-containing peptide linker sequences.

Utilization of New Methods for Antibody Drug Conjugates: Research Progress and Future Prospects

Cancer has become an obvious health problem and scientists focus on this to help the problem. Antibody drug conjugates (ADC) has been considered as an efficient way to treat cancer. There are already many ways to produce ADC, but traditional methods need long and complicated biochemical process. Synthesis methods with high efficiency need to be found. This article aimed to describe three new methods for ADC synthesis, and it came out that all these three methods have high quality and can be used as a common technology to produce ADC. Also, the safety of ADC and several examples of clinical use for ADC were introduced. It provides a reference for ADC synthesis in a relatively simple chemical process for future research. However, there are still some chemical problems that have not been solved, such as azide derivatives are not easy to obtain and they are not stable enough. Future research can focus on the properties of azide derivatives direction.

Abstract 6438: Subcutaneous fat mass predicts progression-free survival in patients treated with antibody-drug-conjugates in early-phase clinical trials

Abstract Background: Antibody drug conjugates (ADCs) have revolutionized the treatment of many solid tumours and hematological diseases. Little is known about the influence of body composition on efficacy and safety of ADCs. Methods: All patients treated with ADCs in early phase clinical trials between 03/2015 and 03/2023 at the Drug Development Department at Gustave Roussy were retrospectively included in the analysis. A deep learning software (Anthropometer3DNet) automatically measured anthropometric parameters in 3D on pretreatment scans, allowing multi-slice measurements of muscle body mass (MBM), fat body mass (FBM), subcutaneous fat mass (SFM) and visceral fat mass (VFM). Other clinical and biological parameters were also retrieved and evaluated. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival analysis was performed using Cox regression models and Kaplan-Meier (KM) estimator. Cut-offs were determined using the maxstat method. Anthropometric parameters’ effect on toxicity was also evaluated using a ROC analysis. Results: A total of 136 patients were treated with ADCs. The most frequent tumor types were non-small cell lung cancer (56 patients, 41%) and colorectal cancer (31 patients, 23%). Median age, ECOG PS, albumin and number of previous lines of treatment were 60.8 years (30 to 85), 1, 42 g/L and 3 respectively. In the overall cohort, median PFS and OS were 2.8 and 8.6 months respectively, 90 (66%) patients had experienced toxicity, of which 46 were grade 3-4. The Royal Marsden Hospital (RMH) prognostic score of 2 or more was significantly associated with worse PFS (HR=2.13, p=0.007) and OS (HR=2.12, p=0.008). The number of treatment lines was significantly associated with worse OS (HR=1.21, p<0.001). For the anthropometric parameters, SFM (HR=0.89, p=0.013) and FBM (HR=0.89, p=0.02) were significantly associated to PFS. Higher SFM (cutoff: 3.3 kg/m2) and FBM (cutoff: 3.6 kg/m2) were significantly associated with longer PFS (mPFS=3.8 vs 2.3 months and 3.7 vs 1.9 respectively). Patients with higher SFM and FBM had numerically but non-significantly longer (mOS=8.5 vs 7.7 months and 8.6 vs 6.4 months respectively). All anthropometric parameters were significantly associated with all-grade toxicity in the univariate but not in the multivariate analysis. None of the parameters were associated with grade 3-4 toxicity. Conclusions: In this large monocenter cohort, 3D measured high SFM and FBM were significantly associated with PFS. Automatic extraction of body composition parameters using AI may help in anticipating the benefits of ADCs in patients included in early-phase clinical trials. Citation Format: Matthieu Delaye, Littisha Lawrance, Younes Belkouchi, Felix Wirth, Pierre Decazes, Alexandre Bône, Kaïssa Ouali, Antoine Hollebecque, Cristina Smolenschi, Rastislav Bahleda, Anas Gazzah, Stéphane Champiat, François-Xavier Danlos, Clémence Hénon, Kristi Beshiri, Madona Sakkal, Aurélien Marabelle, Jean-Marie Michot, Vincent Ribrag, Claudia Parisi, Christophe Massard, Vincent Goldschmidt, Pierre Vera, Santiago Ponce-Aix, Nathalie Lassau, Samy Ammari, Capucine Baldini. Subcutaneous fat mass predicts progression-free survival in patients treated with antibody-drug-conjugates in early-phase clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6438.

Trastuzumab-MMAU Antibody-Auristatin Conjugates: Valine-Glucoserine Linker with Stabilized Maleimide Conjugation Improves In Vivo Efficacy and Tolerability.

Antibody-drug conjugates (ADCs) have shown impressive clinical activity with approval of many agents in hematological and solid tumors. However, challenges remain with both efficacy and safety of ADCs. This study describes novel trastuzumab-auristatin conjugates with the hydrophilic MMAE prodrug MMAU, and optimization of a glycopeptide linker leading to a wider therapeutic window. Trastuzumab was conjugated with auristatin payloads via a series of linkers using a stabilized maleimide handle. The ADCs were characterized in vitro and their relative in vivo anti-tumor efficacies were assessed in HER2+ xenograft models. Relative linker stabilities and the mechanism of linker cleavage were studied using in vitro assays. Toxicity and toxicokinetics of the best performing ADC were evaluated in cynomolgus monkey (cyno). The trastuzumab-MMAU ADC with stabilized glycopeptide linker showed maleimide stabilization and higher resistance to cleavage by serum and lysosomal enzymes compared to a valine-citrulline conjugated trastuzumab ADC (trastuzumab-vc-MMAE). A single dose of 1 or 2 mg/kg of trastuzumab-MMAU at drug-to-antibody ratios (DAR) of 8 and 4 respectively resulted in xenograft tumor growth inhibition, with superior efficacy to trastuzumab-vc-MMAE. Trastuzumab-MMAU DAR4 was tolerated at doses up to 12 mg/kg in cyno, which represents 2- to 4-fold higher dose than that observed with vedotin ADCs, and had increased terminal half-life and exposure. The optimized trastuzumab-MMAU ADC showed potent antitumor activity and was well tolerated with excellent pharmacokinetics in non-human primates, leading to a superior preclinical therapeutic window. The data supports potential utility of trastuzumab-MMAU for treatment of HER2+ tumors.

Dawn of a new era of antibody-drug conjugates and bispecific T-cell engagers for treatment of multiple myeloma: a systematic review of literature.

Multiple myeloma (MM) remains an incurable disease with the majority of patients experiencing disease relapse despite response to initial therapy. Antibody-drug conjugates (ADCs) and bispecific T-cell engagers are innovative immunotherapeutic approaches currently in development for the treatment of MM. This systematic review summarizes the efficacy and safety of ADCs and bispecific T-cell engagers in relapsed refractory (RR) MM patients from 2010 to date. Comprehensive literature search was conducted on PubMed, EMBASE, Wiley Cochrane Library, Web of Science, and Clinicaltrials.gov . A total of 13 studies (n = 529) met inclusion eligibility. All studies were prospective in nature investigating ADCs or bispecific T-cell engagers in RR MM; 10 trials were phase 1 and 3 were phase 2. The median age of patients ranged from 24 to 82 years. Among trials with ADC regimens, the overall response (OR) ranged from 34 to 60% and complete response (CR) ranged from 3 to 6%. The most common non-hematologic adverse event (AE) of ADCs was keratopathy, while anemia and thrombocytopenia were the most common hematological AEs. With bispecific T-cell engagers , ORR ranged from 31 to 83%, CR ranged from 7 to 22%, and partial response (PR) ranged from 5 to 16%. The most common non-hematologic AE of bispecific T-cell engagers was cytokine release syndrome (CRS) while the most common hematological AE was neutropenia. Initial data appears to show good clinical activity and tolerable safety profiles, making ADCs and bispecific T-cell engagers promising agents for RRMM. Future studies with newer combinations and a longer follow-up are needed to determine the precise role of these novel therapies in the evolving paradigm of MM treatment.

Antibody-drug conjugates in breast cancer: the chemotherapy of the future?

Antibody-drug conjugates (ADCs) represent an interesting new class of anticancer agents, capable of exploiting the specificity of monoclonal antibodies toward cellular-antigens for a targeted release of potent cytotoxic drugs, with a potential increased activity and reduced toxicity compared with traditional chemotherapies. The aim of this article is to review the efficacy and safety of ADCs in breast cancer. Following the approval of T-DM1 both in early and advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer, novel anti-HER2 ADCs have been investigated. Some of these compounds, such as the recently FDA-approved trastuzumab deruxtecan, have shown relevant activity in T-DM1-pretreated patients, possibly thanks to the so-called bystander effect, namely the ability to exert cytotoxic activity also against antigen-negative cells. Such feature allows to overcome the HER2 intratumoral heterogeneity in breast cancer and could explain in the preliminary activity demonstrated also in HER2-low breast cancers. However, several ADCs targeting other cancer-associated antigens than HER2 are under development, representing a promising strategy for the treatment of triple-negative tumors, exemplified by the encouraging results of sacituzumab govitecan. ADCs are innovative and effective therapeutic drugs in breast cancer. Research efforts are ongoing to identify novel targets and combination with other treatment modalities, particularly with immunotherapy, to further improve patients' outcomes.

ADCs, as Novel Revolutionary Weapons for Providing a Step Forward in Targeted Therapy of Malignancies.

Antibody drug conjugates (ADCs), as potent pharmaceutical trojan horses for cancer treatment, provide superior efficacy and specific targeting along with low risk of adverse reactions compared to traditional chemotherapeutics. In fact, the development of these agents combines the selective targeting capability of monoclonal antibody (mAb) with high cytotoxicity of chemotherapeutics for controlling the neoplastic mass growth. Different ADCs (more than 60 ADCs) in preclinical and clinical trials were introduced in this novel pharmaceutical field. Various design-based factors must be taken into account for improving the functionality of ADC technology, including selection of appropriate target antigen and high binding affinity of fragment (miniaturized ADCs) or full mAbs (preferentially use of humanized or fully human antibodies compared to murine and chimeric ones), use of bispecific antibodies for dual targeting effect, linker engineering and conjugation method efficacy to obtain more controlled drug to antibody ratio (DAR). Challenging issues affecting therapeutic efficacy and safety of ADCs, including bystander effect, on- and off-target toxicities, multi drug resistance (MDR) are also addressed. 4 FDA-approved ADCs in the market, including ADCETRIS ®, MYLOTARG®, BESPONSA ®, KADCYLA®. The goal of the current review is to evaluate the key parameters affecting ADCs development.

SLAM family proteins as therapeutic targets in multiple myeloma

Reports have described the excellent efficacies of new immunotherapeutic strategies, such as monoclonal antibody (mAb) therapies, in multiple myeloma (MM) patients. Signaling lymphocytic activation molecule family (SLAMF) molecules are expressed strongly on normal lymphocytes and plasma cells from MM patients. The anti-SLAMF7 mAb elotuzumab (ELO) has been approved for the treatment of relapsed/refractory MM (RRMM). In MM patients, a high serum soluble SLAMF7 (sSLAMF7) concentration is associated with aggressive clinical characteristics. This suggests a proliferative function of the SLAMF7-sSLAMF7 interaction that could be inhibited by ELO. SLAMF3 is also expressed strongly and constitutively on myeloma cells. We observed the aggressive characteristics of SLAMF3+ MM in vitro and in vivo. SLAMF3 interacts directly with the adaptor proteins SHP2 and GRB2. A gene expression analysis revealed that SLAMF3 transmits positive signals to MM cells via the MAPK/ERK signaling pathway and that sSLAMF3 levels are increased markedly in advanced MM. Thus, SLAMF3 may be a novel immunotherapeutic target in MM. SLAMF2 and SLAMF6 are also expressed strongly on MM cells, and the safety of antibody-drug conjugates that target these molecules in patients with RRMM is currently under study. Our and others' reports demonstrate the value of SLAMF molecules as promising new targets for antimyeloma immunotherapies.

Antibody-drug conjugates for lung cancer in the era of personalized oncology.

With 9.6 million deaths in 2018, cancer represents one of the most common causes of death, both in men and women. Despite recent advances in the understanding of molecular mechanisms involved in cancer development and progression, treatment options are still limited. Limitations of traditional chemotherapy include the lack of selectivity and the unfavorable safety profile. The efficacy of targeted therapies (e.g., tyrosine kinase inhibitors) is also limited by their cytostatic action, which inhibits tumor cell proliferation without inducing tumor cell death, and by the risk of acquired resistance. Antibody-drug conjugates (ADCs), a newly developed class of engineered anticancer drugs, consist of recombinant monoclonal antibodies against tumor-specific antigens that are covalently bound to cytotoxic agents. They have been designed to overcome the limitations of traditional chemotherapy and targeted therapies by combining the target selectivity of monoclonal antibodies with the high potency of cytotoxic drugs. Currently, ADCs that have received regulatory approval include brentuximab vedotin for CD30-positive Hodgkin lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2-positive breast cancer. However, over 80 novel ADCs are actively being investigated in preclinical studies and early-phase clinical trials. In this review, we will provide a comprehensive overview of the biological rational, efficacy and safety of ADCs as therapeutic agents against non-small cell lung cancer and small cell lung cancer.

Safety and Tolerability of Antibody-Drug Conjugates in Cancer.

Antibody-drug conjugates are monoclonal antibodies attached to biologically active drugs through chemical linkers that deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. Currently, there are about 110 ongoing studies implementing antibody-drug conjugates in the treatment of multiple human malignancies. Antibody-drug conjugates carry a feature of the specificity of a monoclonal antibody and the anti-neoplastic potential of a cytotoxin. The first antibody-drug conjugate was approved in 2001, and the field of antibody-drug conjugates has expanded since then with three more antibody-drug conjugates being added to the market. The complex structure of the antibody-drug conjugate poses a challenge in designing a clinically adequate molecule. Antibody-drug conjugates are usually well tolerated with some predictable adverse reactions, as well as new medical issues, that need careful approach. This review provides an outline of the current status of the efficacy and safety of antibody-drug conjugates in malignant diseases.

A new construct of antibody-drug conjugates for treatment of B-cell non-Hodgkin's lymphomas

The aim of this study was to develop a new class of antibody-drug conjugates (ADCs) with the potential to not only enhance treatment efficacy but also improve tolerability for patients with B-cell lymphomas. Classic ADCs consist of monoclonal antibodies (mAbs) linked to drugs or toxins. They selectively deliver toxic moieties to tumor cells. As such, they greatly improve the therapeutic index compared to traditional chemotherapeutic agents. However, the therapeutic efficacy and safety of ADCs are dependent on linker stability and payload toxicity. Limited payload number on a single antibody (drug-to-antibody ratio, or DAR) has been driving investigators to use extremely toxic agents; however, even very low off-target binding of these ADCs may kill patients. Herein we report a new design of ADCs that consists of rituximab (RTX) and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–epirubicin conjugates. The latter was selectively attached to RTX via reduced disulfide bonds. Such design allows the introduction of a large payload of drug on the antibody without adding attachment sites and without compromising the antigen-targeting ability. The binding of the new conjugate, namely RTX-P-EPI, to Ramos cells (with high CD20 expression) was confirmed. The cytotoxicity of RTX-P-EPI against Raji and Ramos cells was also determined. Interestingly, two-fold inhibition of cell proliferation was observed when using RTX-P-EPI compared with their equivalent physical mixture of RTX and P-EPI. Treatment of male SCID mice bearing subcutaneous Ramos B-cell lymphoma tumors demonstrated that RTX-P-EPI possessed superior efficacy when compared to combination of RTX with chemotherapy EPI (RTX+EPI) and P-EPI (RTX+P-EPI), whereas single RTX and a non-specific conjugate IgG-P-EPI only showed marginal effect. The conjugate RTX-EPI in which EPI was directly attached to RTX demonstrated much less antitumor activity compared with RTX-P-EPI. The results suggest that this new design possesses synergistic potential of immunotherapy combined with established macromolecular therapy; moreover, a conventional chemo-agent could be utilized to generate highly effective ADCs and to achieve lower risk of off-target toxicity.