Authors:

Fei Teng¹, Huanhuan Guo¹, Xinlai Yao¹, Lizhi Qin¹, Lei Shi¹, Xu Lin¹, Yi Gu¹, Xueming Qian¹ 

¹Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, China

Background:

LIV1 is a member of the zinc transporter family. With limited normal tissue expression, LIV1 was found to be overexpressed with high prevalence in breast (93%), prostate (72%) and lung (10%) cancers, and considered as an attractive cell surface target for developing ADC therapeutics. 

We have generated 48D6, a proprietary novel humanized anti-LIV1 mAb with high affinity, specificity, internalization ability, unique epitope and improved pharmacokinetics (PK) profile in mice. 

Then we developed 48D6 based ADCs using glycotransferase mediated site-specific conjugation with Topo I inhibitor (ADC-2) or MMAE (ADC-3), and characterized their anti-tumor activities in preclinical PDX/CDX models and exploratory toxicity in mice.

Results and Conclusions:

Topo I inhibitor payload based ADC-2 displayed strong anti-tumor activities in LIV1 expressing breast and NSCLC PDX models.

For LIV1 expressing prostate PDX models, two doses of ADC-2 did not inhibit tumor growth significantly. After MMAE-based ADC-3 replaced ADC-2 from the 3rd dose, ADC-3 inhibited the growth of the prostate tumor significantly. In a LIV1 high expressing prostate PDX, the tumor growth was suppressed by ADC-3 for over 70 days after the dosing was stopped on Day 28.

In exploratory tox study, ADC-2 were well tolerated following repeated administrations in mice at all doses tested. Slight lesions were observed in 60 mg/kg group during the treatment period and fully recovered at the end of the recovery period. Based on these results, the maximum tolerated dose (MTD) of ADC-2 in mice was determined at 60 mg/kg.

LIV1 targeting ADC-2 and ADC-3 exhibited strong anti-tumor activities as monotherapy in PDX models and the anti-tumor activity is further enhanced by checkpoint inhibitor. ADC-2 displayed excellent tolerability profile in mice. These results support further investigation of our LIV1 ADCs in LIV1 positive solid tumors.