SLC46A3 as a Potential Predictive Biomarker for Antibody–Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads

Kinneer, Krista; Meekin, John; Tiberghien, Arnaud; Tai, Yu‐Tzu; Phipps, Sandrina; Kiefer, Christine M.; Rebelatto, Marlon C.; Dimasi, Nazzareno; Moriarty, Alyssa; Papadopoulos, Kyriakos P.; Sridhar, Srinivas; Gregson, Stephen J.; Wick, Michael J.; Masterson, Luke A.; Anderson, Kenneth C.; Herbst, Ronald; Howard, Philip W.; Tice, David A.

doi:10.1158/1078-0432.ccr-18-1300

Cited by 63 publications

(63 citation statements)

References 56 publications

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“…Indeed, the safety profile of ADCs depends on the toxic payload used. For certain ADC constructs, extracellular cleavage of the ADC before target cell penetration could lead to premature liberation of the toxic payload and negative effects on healthy cells, but the use of noncellpermeable payloads (e.g., MMAF) or non-cleavable linkers can reduce this concern [17,59]. Similar to bispecific antibody constructs, ADCs can induce immunogenic responses against myeloma cells, which could help promote durable endogenous antimyeloma activity [17,31].…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

“…ADCs are tumor-associated antigen (TAA)-targeted mAbs conjugated to toxic payloads, such as tubulin polymerization inhibitor monomethyl auristatin F (MMAF), pyrrolobenzodiazepine (PBD), or the RNA polymerase II inhibitor α-amanitin, using a cleavable or non-cleavable linker[17,31,59,60]. Once bound to TAA-expressing target cells, ADCs are internalized and the toxic payload is released to induce DNA damage and cell death(Fig.…”

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confidence: 99%

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B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

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confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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“…The next set of experiments used PBD SG3552 and its linker-derivative SG3376 (45, 46) (Figure 1B). This toxin-linker combination was chosen as it was designed to have fewer off-target effects (45, 47) and was shown to be more potent against trypanosomes in preliminary experiments. Three antibody-SG3376 conjugates were prepared from Tb074, Tb085 and NIP228 and all were tested for trypanocidal activity as above but using HpHbR wild type and −/− cell lines (Figure 3B and Table 1).…”

Section: Resultsmentioning

confidence: 99%

A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis

MacGregor¹,

González-Muñoz²,

Jobe³

et al. 2019

Preprint

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22Infections of humans and livestock with African trypanosomes are treated with drugs 23 introduced decades ago that are not always fully effective and often have severe 24 side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has 25 been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is 26 completely effective against Trypanosoma brucei in the standard mouse model of 27 infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and 28 shown to be internalised in a receptor-dependent manner. Antibodies were 29 conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at 30 picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR 31 antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days 32 with no re-emergence of infection over a subsequent time course of 77 days. These 33 experiments provide a demonstration of how ADCs can be exploited to treat 34 protozoal diseases that desperately require new therapeutics. 35 36 Author Summary 37Here we show that antibody-drug conjugates (ADCs) can be re-purposed from 38 cancer immunotherapeutics to anti-protozoals by changing the specificity of the 39 immunoglobulin to target a trypanosome cell surface receptor. Trypanosomes were 40 used as a model system due to the availability of receptor null cell lines that allowed 41 the unambiguous demonstration that ADCs targeted to a parasite surface receptor 42 could be specifically internalised via receptor-mediated endocytosis. A single low 43 dose of the resulting ADC was able to cure a stage 1 mouse model of trypanosome 44 infection. We have used toxins and conjugation chemistry that are identical to anti-45 3 cancer ADCs demonstrating the ability to piggy-back onto the huge research efforts 46 and resources that are being invested in the development of such ADCs. 47The potential for development of ADCs against a wide range of human pathogens is 48 vast, where only epitope binding sites need vary in order to provide selectivity. This 49 provides a far-reaching opportunity for the rapid development of novel anti-50 protozoals for the targeted killing of a wide range of pathogens that cause disease 51 worldwide, especially in developing countries.

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“…Using established breast cancer cell lines, several groups have identified mechanisms of resistance to T-DM1. These include downregulation of HER2 [7][8][9], activation of alternative RTKs or intracellular signaling pathways downstream of HER2 [7], upregulation of Bcl-2/X L [8], defective intracellular routing [9] defective lysosomal function [10][11][12] and upregulation of multidrug resistance transporters [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

The Second Generation Antibody-Drug Conjugate SYD985 Overcomes Resistances to T-DM1

Nadal-Serrano

Morancho

Escrivá-de-Romaní

et al. 2020

Cancers

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Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer. T-DM1 consists of trastuzumab covalently linked to the cytotoxic maytansinoid DM1 via a non-cleavable linker. Despite its efficacy, primary or acquired resistance frequently develops, particularly in advanced stages of the disease. Second generation ADCs targeting HER2 are meant to supersede T-DM1 by using a cleavable linker and a more potent payload with a different mechanism of action. To determine the effect of one of these novel ADCs, SYD985, on tumors resistant to T-DM1, we developed several patient-derived models of resistance to T-DM1. Characterization of these models showed that previously described mechanisms-HER2 downmodulation, impairment of lysosomal function and upregulation of drug efflux pumps-account for the resistances observed, arguing that mechanisms of resistance to T-DM1 are limited, and most of them have already been described. Importantly, SYD985 was effective in these models, showing that the resistance to first generation ADCs can be overcome with an improved design.

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SLC46A3 as a Potential Predictive Biomarker for Antibody–Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads

Cited by 63 publications

References 56 publications

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis

The Second Generation Antibody-Drug Conjugate SYD985 Overcomes Resistances to T-DM1

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