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Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 Page 209

NEW GENERATION HER2 TARGETED ADCS
XMT-1522 employs a novel human anti-HER2 antibody conjugated with an auristatin (microtubule
polymerization inhibitor)-derivative payload, Auristatin F-Hydroxypropylamide, via a biodegradable
[33]
hydrophilic polymer, which increased drug to antibody ratio of XMT-1522 to 10-15 . In pre-clinical trials,
XMT-1522 exhibited anti-tumour efficacy in highly HER2-expressing gastric cancer models. Tumour
regression was seen either with XMT-1522 alone or with the XMT-152/trastuzumab/pertuzumab triple
[34]
combination . A dose escalation phase I study (NCT02952729) in patients with HER2-expressing breast,
2
lung and gastric cancers demonstrated that XMT-1522 was well-tolerated up to the 21.3 mg/m dose level
with only grade 1 or 2 AE observed. The common AE were impaired liver function, fatigue, nausea,
vomiting, reduced appetite and headache. MTD was not established in this study as no dose limiting toxicity
was identified. As of February 1st 2018, there are 19 patients enrolled where DCR was 83% (5/6) for patients
2
dosed at 16 or 21.3 mg/m . Two stable disease (SD) outcomes were seen in gastric cancer patients and others
in breast cancer patients. Dose escalation continues with more results expected .
[35]
MEDI-4276 is another ADC approach to HER2 expressing tumours. MEDI-4276 is a biparatopic ADC that
targets two different epitopes on HER2, with site-specific conjugation to a tubulysin-based microtubule
[36]
inhibitor. MEDI-4276 utilizes a cleavable linker that enables it to mediate bystander killing activity . Pre-
clinical trials indicated that MEDI-4276 has anti-tumour activity in vitro, including in T-DM1 resistant cells.
A phase I/II dose escalation trial (NCT02576548) had recruited 43 patients with HER2-expressing breast
or gastric cancers by November 2017. MTD at 0.9 mg/kg showed dose limiting toxicity of grade 3 elevated
alanine aminotranferase (ALT)/aspartate aminotransferase (AST) or grade 3 diarrhea. Common AE were
nausea, fatigue, vomiting and elevated ALT/AST. In this study, MEDI-4276 exhibited anti-tumour activity
[37]
with 1 complete response, 1 partial response (PR) and 12 (28%) SD . A further report is awaited.

SYD985 consists of trastuzumab conjugated to the DNA alkylating agent duocarmycin via a cleavable
linker. Multiple pre-clinical trials strongly suggested that SYD985 had extended anti-tumour activity in
HER2 low-expressing or HER2 negative breast, gastric, ovarian or uterine cancer cell lines, when compared
directly to T-DM1. Unlike T-DM1, SYD985 is able to induce efficient bystander killing effect in vivo, which
contributes to significantly improved anti-tumour activity of SYD985 when compared to T-DM1 [38-41] . A
phase I dose expansion cohort study (NCT02277717) showed promising efficacy of SYD985 in heavily
pretreated breast cancer patients, including hormone-receptor positive and triple negative breast cancer.
The MTD was 2.4 mg/kg with a manageable safety profile, mainly characterized by grade 1/2 AE of fatigue,
dry eyes, conjunctivitis and increased lacrimation. Dose limiting toxicity included grade 3/4 AE including
neutropaenia and conjunctivitis. The ORRs were 27% and 40% respectively in hormone-receptor positive and
triple negative breast cancer patients; several patients continue on SYD985. Further dose expansion date is
[42]
pending in gastric cancer patients .

ARX-788 is a site-specific ADC conjugating amberstatin (tubulin inhibitor) to a HER2 antibody at two
specific sites via a non-cleavable linker. Pre-clinical studies reported that ARX-788 demonstrated increased
anti-tumour activity in breast, ovarian, lung and gastric cancer xenograft models compared to T-DM1.
Unlike T-DM1, the site-specific conjugated form of ARX-788 has increased stability of up to 3 weeks which
[43]
improved its therapeutic window and anti-tumour activity . There are currently two dose escalation phase I
trials recruiting patients with HER2-expressing breast and gastric cancers (NCT03255070 and NCT02512237)
with the intention to identify a safety profile of ARX-788 and potential anti-tumour efficacy.

ADCT-502 is made of an engineered version of trastuzumab, site-specifically conjugated to a highly cytotoxic
pyrrolobenzodiazepine-based drug, tesirine, via a protease cleavable linker. It has a drug to antibody ratio
of 1.7 and demonstrates bystander killing effect in vitro. There is superiority in anti-tumour effect of ADCT-
[44]
502 compared to T-DM1 in various tumour xenografts, including those with low HER2 expression levels .