There has been huge progress in the discovery of targeted cancer therapies in recent years. However, even for the most successful and impactful cancer drugs which have been approved, both innate and acquired mechanisms of resistance are commonplace. These emerging mechanisms of resistance have been studied intensively, which has enabled drug discovery scientists to learn how it may be possible to overcome such resistance in subsequent generations of treatments. In some cases, novel drug candidates have been able to supersede previously approved agents; in other cases they have been used sequentially or in combinations with existing treatments. This review summarizes the current field in terms of the challenges and opportunities that cancer resistance presents to drug discovery scientists, with a focus on small molecule therapeutics. As part of this review, common themes and approaches have been identified which have been utilized to successfully target emerging mechanisms of resistance. This includes the increase in target potency and selectivity, alternative chemical scaffolds, change of mechanism of action (covalents, PROTACs), increases in blood-brain barrier permeability (BBBP), and the targeting of allosteric pockets. Finally, wider approaches are covered such as monoclonal antibodies (mAbs), bispecific antibodies, antibody drug conjugates (ADCs), and combination therapies.

Challenges and Opportunities in Cancer Drug Resistance.

The DARPin® drug platform was established with a vision to expand the medical use of biologics beyond what was possible with monoclonal antibodies It is based on naturally occurring ankyrin repeat domains that are typically building blocks of multifunctional human proteins The platform allows for the generation of diverse, well-behaved, multifunctional drug candidates Recent clinical data illustrate the favorable safety profile of the first DARPin® molecules tested in patients With the positive phase III results of the most advanced DARPin® drug candidate, abicipar, the DARPin® drug platform is potentially about to achieve its first marketing approval This review highlights some of the key milestones and decisions encountered when transforming the DARPin® platform from an academic concept to a biotech drug pipeline engine

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Beyond Antibodies: The DARPin ® Drug Platform.

Engineering of binding functions into proteins

Peptides and proteins are two classes of molecules with attractive possibilities for therapeutic applications. However, the bottleneck for the therapeutic application of many peptides and proteins is their short halflives in vivo, typically just a few minutes to hours. Half-life extension strategies have been extensively studied and many of them have been proven to be effective in the generation of long-acting therapeutics with improved pharmacokinetic and pharmacodynamic properties. In this review, we summarize the recent advances in half-life extension strategies, illustrate their potential applications and give some examples, highlighting the strategies that have been used in approved drugs and for drugs in clinical trials. Meanwhile, several novel strategies that are still in the process of discovery or at a preclinical stage are also introduced. In these strategies, the two most frequently used half-life extension methods are the reduction in the rate of renal clearance or the exploitation of the recycling mechanism of FcRn by binding to the albumin or IgG-Fc. Here, we discuss half-life extension strategies of recombinant therapeutic protein via genetic fusion, rather than chemical conjugation such as PEGylation. With the rapid development of genetic engineering and protein engineering, novel strategies for half-life extension have been emerged consistently. Some of these will be evaluated in clinical trials and may become viable alternatives to current strategies for making next-generation biodrugs.

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Recent Advances in Half-life Extension Strategies for Therapeutic Peptides and Proteins.

Recent advances in HER2-targeted delivery for cancer therapy.

Background: MP0274 is a four domain, trispecific, biparatopic, HER2-targeted Designed Ankyrin Repeat Protein (DARPin®) drug candidate. M0274 binds to domains II and IV of HER2 at different sites from trastuzumab and pertuzumab, and to human serum albumin for an extended half-life. MP0274 displays a unique mode of action in preclinical models by directly inducing apoptosis in HER2-addicted cancer cells. Compared to anti-HER2 monoclonal antibodies, preclinical studies revealed no additional safety signals and no maximum tolerated dose was reached. Trial Design: This is a first-in-human study with 2 parts. The dose escalation part of the study, follows a classical 3+3 dose escalation approach, including one extra cycle for exploration of specific PK characteristics, and will establish the recommended dose (RD) for further development based on safety, pharmacokinetics (PK), and preliminary efficacy. The extension part is designed to confirm safety and further estimate efficacy at the RD in additional patients. MP0274 monotherapy will be administered as infusion over one hour every 3 weeks until disease progression. Eligibility Criteria: The study population for this first-in-human study is HER2-positive cancer patients who have progressed after standard therapy for advanced disease. Inclusion/exclusion criteria are similar to those in studies with anti-HER2 antibodies. Specific Aims: The primary objective is to assess safety and tolerability. Secondary objectives are PK, preliminary anti-tumor efficacy (RECIST), and characterization of immunogenicity. Biomarker evaluation include exploratory markers such as PIK3CA, BCL2, p53, PTEN and p21 in both tissue or plasma (ctDNA), investigation of drug induced apoptotic markers as well as additional translational research. This may help get a deeper insight into MP02749s mode of action and into potential resistance mechanisms. MP0274 may have the potential to be active against all HER2-dependent tumors including those that are resistant to trastuzumab and pertuzumab due to incomplete signaling inhibition or inadequate ADCC functionality. MP0274 could be a valid treatment option for HER2 positive cancers. Statistical Methods: Due to being of non-comparative nature, no inferential statistical analysis will be applied in either the escalation or the expansion part of this study. Results will be listed and summarized by dose regimen using descriptive statistics. An interim evaluation of safety, tolerability and preliminary anti-tumor activity will be performed after 14 patients have been dosed at RD at least once and have completed end of Cycle 4. An interim analysis will be performed once all planned 29 patients have been dosed at RD at least once and completed end of Cycle 7 (pre-Cycle 8) tumor assessment. The final statistical analysis will occur after all patients have discontinued treatment for any reason and completed safety follow-up. Present Accrual and target accrual: Currently recruitment is planned in UK, Germany, and Switzerland. Target accrual is 36 evaluable patients. Citation Format: Baird R, Omlin A, Kiemle-Kallee J, Fiedler U, Zitt C, Feurstein D, Herbst J, Dawson K, vom Baur E, Stumpp M, Hermann F, Harstrick A, Schneeweiss A. MP0274-CP101: A phase 1, first-in-human, single-arm, multi-center, open-label, dose escalation study to assess safety, tolerability, and pharmacokinetics of MP0274 in patients with advanced HER2-positive solid tumors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-03-02.

Abstract OT1-03-02: MP0274-CP101: A phase 1, first-in-human, single-arm, multi-center, open-label, dose escalation study to assess safety, tolerability, and pharmacokinetics of MP0274 in patients with advanced HER2-positive solid tumors

A Schneeweiss

Papers

Abstract OT1-03-02: MP0274-CP101: A phase 1, first-in-human, single-arm, multi-center, open-label, dose escalation study to assess safety, tolerability, and pharmacokinetics of MP0274 in patients with advanced HER2-positive solid tumors