Click on a question to see the answer.

Q: Doesn’t manufacturing both cGMP CAR-T cells and cGMP MicAbodies double the cost and make the product not viable commercially?

A: The cost to manufacture a MicAbody with a new targeting domain (IgG) will be less than manufacturing and QC releasing a new CAR-T cell, either autologous or allogeneic, with a new targeting domain. In addition, a portfolio of individual MicAbodies with commonly indicated targets could be manufactured and approved, and then the desired MicAbody would be selected from the portfolio of approved MicAbodies for use in multiple patients without changing the patients’ convertibleCAR-T cells.

Q: Rather than developing a 2 components system to direct T-cells to target cells, why not simply use a bispecific antibody that binds to CD3 on T-cells?

A: The simple answer is in order to capture the efficacy of CAR-T’s and the flexibility of bispecifics—under circumstances where both the activity and targeting of convertibleCAR-T’s can be precisely controlled by the bispecifics.

Furthermore, efficacy of CD3-bispecifics is dependent on endogenous CD3+ T-cells, which are subject to at least 3 variables differing widely between patients:  the quantity of T-cells, the quality of T-cells (exhausted, tolerized, etc.), and their sensitivity to suppression by environmental factors. All endogenous CD3+ T-cells opsonized by anti-CD3 bispecific antibodies also become sensitive to unintended activation, again by environmental factors.  CAR-T cells, particularly allogeneic cells, are independent of endogenous T-cells, and convertibleCAR-T cells are inert until activated by a cognate orthotopic MicAbody.

Q: Why do you expect MicAbodies will access solid tumors and be efficacious when typical monoclonal antibodies are ineffective because they don’t penetrate solid tumors?

A: Monoclonal antibodies are efficacious in numerous different solid tumors.  MicAbodies can be dosed as are efficacious monoclonals, followed by convertibleCAR-T cells.  And the convertibleCAR-T cells should respond to inflammatory signals from solid tumors as do natural T-cell populations.

Q: Isn’t it as easy and as cost-effective to change CAR-T cell targeting by just producing another CAR-T cell as to make another MicAbody for a convertibleCAR-T cell?

A: The cost to manufacture a MicAbody with a new targeting domain (IgG) will be less than manufacturing and QC releasing a new CAR-T cell, either autologous or allogeneic, with a new targeting domain.  In addition, a portfolio of individual MicAbodies with commonly indicated targets could be manufactured and approved, and then the desired MicAbody would be selected from the portfolio of approved MicAbodies for use in multiple patients without changing the patients’ convertibleCAR-T cells.

Q: Why is a convertibleCAR-T cell safer than the typical pre-targeted CAR-T cell?

A: In the absence of the targeting MicAbody, convertibleCAR-T cells cannot recognize a target and thus will remain inert.

Q: Next generation CAR-T cells entering preclinical and clinical stages contain effective on/off/kill switches, so why use a complicated 2-component system of convertibleCAR-T cells plus MicAbody to control activity by dosing?

A: On-off switches in CAR-cells may be effective but also require dosing with another “drug” for control.  Additional advantages of MicAbodies include the stabilities of human-derived, full IgG targeting domains.  The ability to switch or multiplex targeting without producing multiple CAR cells is not provided by current CAR cell technologies.

Q: How does convertibleCAR technology improve CAR-T cell persistence in vivo?

A: A major impediment to the persistence of current CAR therapies is the use of mouse-derived scFv receptors, which elicit robust ADA responses. convertibleCAR components are derived from human proteins and should avoid strong ADA responses, thereby improving efficacy and persistence.

Q: Why target CD20 and CD19 when those medical needs are already satisfied by monoclonal antibodies and soon-to-be approved CD-19 targeted CAR-T cells?

A: Since CD19 and CD20 are validated targets for B-cell malignancies, for proof-of-concept in humans the risk of failure in the due to an invalid target will be greatly reduced.  CD19 targeted CAR-T cells have induce very impressive, high rates of responses in patients with refractory B-cell hematologic malignancies; however, long-term disease-free survival is well shy of 100%, and the malignant cells of many relapsed patients lack CD19.  CD20-scFv Car-T cells have not shown the same efficacy as have CD19 CAR-T cells, apparently because of the instability of the CD20-based scFv CAR resulting in “exhaustion” of the T-cell.  CD20 MicAbodies are as stable in vitro and in vivo as Rituximab. Patients with relapsing CD19-negative B-cell malignancies could be treated with convertibleCAR-T cells plus CD20 MicAbody.  Primary treatment with convertibleCAR-T cells could commence with a CD19 or a CD20 MicAbody—or both—to address the initial and long-term failures.

Q: Aren’t MicAbodies going to be immunogenic since they are modified human proteins?

A: Possibly some patients depending on their MHC genotypes and state of immune-compromise will generate an immune response.  The modified, non-natural ligands of the MicAbodies contain 7 or fewer substitutions (less than 5% of the protein sequence), far fewer mutations than typical CDRs of therapeutic antibodies. However, we have generated MicAbodies based on different natural ligands of NKG2D so as to be able to by-pass an immune response to an initial ligand by simply switching the MicAbody—with or without changing the targeting domain.  Only 1 or 2 amino acid changes were made to generate the non-natural, inert NKG2D receptors of convertibleCAR cells.    CAR-T cells currently in the clinic are based on scFv’s derived from mouse antibodies; clearly MicAbodies and the non-natural, inert NKG2D receptors will be significantly less immunogenic.

Q: Does the modified ligand of the MicAbody that binds inert NKG2D bind to any normal human molecule?

A: This is an active area of investigation and will be pursued in IND enabling toxicology.

Q: Won’t the antibody portions of the MicAbodies infringe existing composition of matter patents?

A: Perhaps; but numerous mAb have not been patented or are off-patent, and many of the issued patents claiming mAbs are sequence-specific and not target-specific, thereby leaving opportunities for our use of newly discovered, non-natural mAb’s, e.g. generated by phage- or yeast-display technologies. Importantly, we also intend to leverage through strategic partnerships or licensing the vast numbers of novel mAbs.

Q: Does the company have any intellectually property protection of MicAbodies and convertibleCAR-T cells?

A: U.S. and PCT patent applications were published in early February 2017. See WO/2017/024131.

Q: Does the Company have access to or freedom to operate in the CAR-cell space?

A: Very good question and very complex issue.  Yearsl after many journal publications and the filings of now expired patents, there have been hundreds of patents filed and tens of U.S. patents issued claiming CAR’s and CAR-cells with the same unnatural component parts, e.g. TCR CD3 zeta, CD28, 4-1BB, in spite of the obvious prior art. Clearly there must be freedom-to-operate deploying such component parts to create CAR’s with variations in the targeting domains, connectors, transmembrane components, etc. Furthermore, it is possible, at least in the U.S., to obtain new patent claims, very narrow as they are, incorporating these previously disclosed domains. There are several inter partes reviews and litigation underway but those appear to be the result of companies in pivotal clinical trials directly using another’s claimed sequences.

Q: What are the advantages of the convertibleCAR-T cell and MicAbody system over the competition; and particularly UNUM?

A: See the power points describing advantages versus UNUM and other entities that we consider competitive in the CAR space. A unique safety liability of UNUM’s high affinity CD16 receptor CAR is that the CAR-cell will be activated by and attack any off-target cell that is opsonized by any normal CD16-binding IgG. The inert NKG2D of the convertibleCAR cannot bind any natural ligands and thus is without an analogous safety liability in the presence of even an excess of natural ligands, soluble or cell surface displayed, due to its privileged partnering with the orthogonal MicAbody.

Q: How is the convertibleCAR-T platform different from that of CALIBR’s “switch” platform?

A: There are two important aspects shared by the two platforms.  First, each can provide via an adapter, a dose-dependent activation of their respective CAR-T cells. Second, each provides a means of converting or switching the targeting of the CAR-T cells without starting over with CAR-T cell engineering and production.  But there are differences on several fronts.

The extracellular portion of the CALIBR chimeric receptor is comprised of an scFv that binds one end of the CALIBR adapter molecule. In the context of CAR-T cells, scFv’s can be unstable, leading to “T-cell exhaustion”.  Pete Schultz is a creative chemist, and CALIBR’s construction of the bispecific adapters which bridge the CAR-T cell and the targeted cell to generate the necessary immunologic synapse are chemistry heavy. The CAR-binding ends of the adapters are comprised of synthetic, non-human motifs attached to the targeting domain via one or more clever, complex chemical modifications.  The numerous combinatorial construction options result in different effects on in vitro potencies and efficacies against different targets, effects that are not consistently predictive of in vivo results (in mice).  Thus, processes of selecting and optimizing clinical candidates, and manufacturing and QC releasing products would not likely be straight-forward or standardized.

The extracellular portion of the convertibleCAR-T cell is comprised of the ectodomain of the non-polymorphic human NKG2D receptor containing a single amino acid change; this inert NKG2D is inert because it does not bind nor can it be activated by any of its natural human ligands. The adapter of the convertibleCAR system, a MicAbody, includes a natural human ligand of NKG2D modified by protein engineering to bind only to the inert NKG2D receptor; this orthogonal ligand contains fewer amino acid changes than does a CDR of a typical human antibody. In order to create the MicAbody that orthogonal ligand is by simple recombinant DNA technology fused to a complete antibody for targeting. Accordingly, MicAbodies can be produced by the same well-known processes and QC analytics used to manufacture and release monoclonal antibodies.  The simplicity of construction and manufacturing of the convertibleCAR parts, all human-derived, should be expected to have reduced cost and exhibit minimal immunogenicity.

Q: When will the first convertibleCAR-T cell and MicAbody system be in the clinic?

A: We can anticipate entering the clinic in 2018 given an appropriate partnership per the above questions and answers.

Q: Can preclinical safety and efficacy studies of the human convertibleCAR-T cell and MicAbody system be conducted in a non-human primates (“NHP”)?

A: Yes; both Rhesus and Cynomolgus macaques possess an NKG2D receptor along with a repertoire of cognate natural ligands. As expected, these natural ligands do not bind to our engineered inert human NKG2D receptor nor do the non-natural human ligands of MicAbodies engage with NHP NKG2D.  Furthermore, both NHP species express CD20 homologs that can be targeted by our proprietary CD20 MicAbody.  As a consequence, a human convertibleCAR-T cell with a CD20-targeting MicAbody can be studied in either NHP for preclinical evaluation of safety and efficacy, i.e. reduction of CD20-expressing peripheral lymphocytes as a biomarker.

Q: How complicated will the GLP toxicology and the Phase I study be with the 2-component convertibleCAR-T cell and MicAbody system?

A: The GLP toxicology required by the FDA will not be evident until we have a pre-pre-IND meeting, likely to be scheduled next quarter.  We have been told by parties conducting PoC studies for autologous CAR-T’s that the flexibility of the Agency is surprising.  Worse case will require demonstrating in 2 species the safety of the inert CAR-T cells and the safety of the MicAbody candidate, as well as safety of the combination.  The safety of the CAR cells and the MicAbody can be temporally conducted in parallel, and as soon as the NOAEL for the inert CAR cells has been established, the NOAEL for the MicAbody in combination with CAR-T cells can follow.  The FDA currently has extensive familiarity and experience with GLP toxicology of CAR-T cells.

Q: Can the company manufacture autologous and allogeneic convertibleCAR-T cells?

A: We plan to partner with entities that have that capability or contract with emerging CMO’s capable of non-commercial scale production of CAR-Ts.

Q: How manufacturable are MicAbodies?

A: Production is comparable to typical monoclonal antibodies at laboratory scale by transient expression in HEK293 or CHO cells and in stable CHO cells.

Q: Are MicAbodies stable at ambient temperatures; can they be lyophilized for commercial purposes?

A: They are stable at ambient and 4°C as well as frozen, typical of a mAb. We have not yet needed or tried to lyophilize.

Q: What are the pharmacokinetic and pharmacodynamics properties of MicAbodies in humans?

A: Those properties will be determined during Phase I clinical studies.  In mice they have properties typical of human mAbs.