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Protein design Abstract Small molecules and antibodies each have advantages and limitations as therapeutics. Biochemical characterization demonstrates that the chemibodies present superior DPP-IV inhibition compared to either small molecule or antibody component alone. We validated our design by successfully solving a co-crystal structure of a chemibody in complex with DPP-IV, confirming specific binding of the small molecule portion at the interior catalytic site and the Fab portion at the protein surface. The discovery of chemibodies presents considerable potential for novel therapeutics that harness the power of both small molecule and antibody modalities to achieve superior specificity, potency, and pharmacokinetic properties. Introduction Human antibodies are highly effective at binding protein surfaces, but have less success when a deep, concave pocket is the desired site of drug action 1. On the other hand, small molecules have traditionally been used in targeting deep, concave pockets.
If a mailing address is not furnished or cannot be determined or if service by mail or other public means is returned without acceptance, the complaint and summons shall promptly be delivered to the sheriff or his deputy who, unless otherwise directed, shall serve the summons. The summons and complaint shall be served together unless otherwise ordered by the court. When service of summons is made by publication, the complaint shall not be published. When jurisdiction over a party is dependent upon service of process by publication or by his appearance, summons and complaint shall be deemed to have been served at the end of the day of last required publication in the case of service by publication, and at the time of appearance in jurisdiction acquired by appearance.
Whenever the summons and complaint are not served or published together, the summons shall contain the full, unabbreviated title of the case. Process may be served anywhere within the state and outside the state as provided in these rules. Whenever service is made under Clause 3 or 4 of subdivision A , the person making the service also shall send by first class mail, a copy of the summons and the complaint to the last known address of the person being served, and this fact shall be shown upon the return.
Service upon an individual known to be an infant shall be made upon his next friend or guardian ad litem, if service is with respect to the same action in which the infant is so represented.
If there is no next friend or guardian ad litem, service shall be made upon his court-appointed representative if one is known and can be served within this state. If there is no court-appointed representative, service shall be made upon either parent known to have custody of the infant, or if there is no parent, upon a person known to be standing in the position of custodian or parent. The infant shall also be served if he is fourteen  years of age or older.
In the event that service, as provided above, is not possible, service shall be made on the infant. Service upon an individual who has been adjudged to be of unsound mind, otherwise incompetent or who is believed to be such shall be made upon his next friend or guardian ad litem, if service is with respect to the same action in which the incompetent is so represented.
If there is no court-appointed representative, then upon the named party and also upon a person known to be standing in the position of custodian of his person.
Nothing herein is intended to affect the duty of a party to inform the court that a person is an infant or incompetent. An appearance by a court-appointed guardian, next friend or guardian ad litem or his attorney shall correct any defect in service under this section unless such defect be challenged.
Summons: Service upon institutionalized persons Service of summons upon a person who is imprisoned or restrained in an institution shall be made by delivering or mailing a copy of the summons and complaint to the official in charge of the institution. It shall be the duty of said official to immediately deliver the summons and complaint to the person being served and allow him to make provisions for adequate representation by counsel.
The official shall indicate upon the return whether the person has received the summons and been allowed an opportunity to retain counsel. Service upon persons in actions for acts done in this state or having an effect in this state. In addition, a court of this state may exercise jurisdiction on any basis not inconsistent with the Constitutions of this state or the United States.
Jurisdiction under this rule is subject to the power of the court to order the litigation to be held elsewhere under such reasonable conditions as the court in its discretion may determine to be just. The court may, on motion and notice to the parties, modify an order granting a stay or dismissal under this subsection and take any further action in the proceeding as the interests of justice may require.
If the moving party violates a stipulation required by subsection D , the court shall withdraw the order staying or dismissing the action and proceed as if the order had never been issued. Notwithstanding any other law, the court shall have continuing jurisdiction for the purposes of this subsection. Summons: Service upon resident who cannot be found or served within the state When the person to be served is a resident of this state who cannot be served personally or by agent in this state and either cannot be found, has concealed his whereabouts or has left the state, summons may be served in the manner provided by Rule 4.
When shown upon an affidavit or in the return, that service upon an organization cannot be made as provided in subdivision A or B of this rule, service may be made by leaving a copy of the summons and complaint at any office of such organization located within this state with the person in charge of such office.
If service cannot be made upon such agent, because there is no address furnished as required by statute or valid agreement or his whereabouts in this state are unknown, then his principal shall be deemed to have appointed the Secretary of State as a replacement for the agent and service may be made upon the Secretary of State as provided in Rule 4.
Summons: Service of pleadings or summons on Attorney General Service of a copy of the summons and complaint or any pleading upon the Attorney General under these rules or any statute shall be made by personal service upon him, a deputy or clerk at his office, or by mail or other public means to him at such office in the manner provided by Rule 4.
In any action involving a res situated within this state, service may be made as provided in this rule. The court may render a judgment or decree to the extent of its jurisdiction over the res. Whenever, under these rules or any statute, service is made upon the Secretary of State or any other governmental organization or officer, as agent for the person being served, service may be made upon such agent as provided in this rule.
Summons: Registered or certified mail Whenever service by registered or certified mail or other public means by which a return receipt may be requested is authorized, the clerk of the court or a governmental agent under Rule 4. In his return the clerk of the court or the governmental agent shall show the date and place of mailing, a copy of the mailed or electronically-transmitted return receipt if and when received by him showing whether the mailing was accepted or returned, and, if accepted, by whom.
The return along with the receipt shall be promptly filed by the clerk with the pleadings and become a part of the record. If a mailing by the clerk of the court is returned without acceptance, the clerk shall reissue the summons and complaint for service as requested, by the person seeking service. Whenever service is made by delivering a copy to a person personally or by leaving a copy at his dwelling house or place of employment as provided by Rule 4.
Service shall be effective if made by a person not otherwise authorized by these rules, but proof of service by such a person must be made by him as a witness or by deposition without allowance of expenses therefor as costs.
The person to whom the summons is delivered for service must act promptly and exercise reasonable care to cause service to be made.
A sheriff, his deputy, or any full-time state or municipal police officer may serve summons in any county of this state if he agrees or has agreed to make the service. When specially requested in the praecipe for summons, the complaint and summons shall be delivered to such officer by the clerk or the attorney for the person seeking service.
In no event shall any expenses agreed upon under this provision be assessed or recovered as costs or affect court costs otherwise imposed for regular service.
A summons may be served in any county in this state. If service is to be made in another county, the summons may be issued by the clerk for service therein to the sheriff of such county or to a person authorized to make service by these rules.
Personal service, when permitted by these rules to be made outside the state, may be made there by any disinterested person or by the attorney representing the person seeking such service. The expenses of such person may be assessed as costs only if they are reasonable and if service by mail or other public means cannot be made or is not successful.
In any action where notice by publication is permitted by these rules or by statute, service may be made by publication. Summons by publication may name all the persons to be served, and separate publications with respect to each party shall not be required.
The person seeking such service, or his attorney, shall submit his request therefor upon the praecipe for summons along with supporting affidavits that diligent search has been made that the defendant cannot be found, has concealed his whereabouts, or has left the state, and shall prepare the contents of the summons to be published.
The summons shall be signed by the clerk of the court or the sheriff in such manner as to indicate that it is made by his authority. The summons shall be published three  times by the clerk or person making it, the first publication promptly and each two  succeeding publications at least seven  and not more than fourteen  days after the prior publication, in a newspaper authorized by law to publish notices, and published in the county where the complaint or action is filed, where the res is located, or where the defendant resides or where he was known last to reside.
If no newspaper is published in the county, then the summons shall be published in the county in this state nearest thereto in which any such paper may be printed, or in a place specially ordered by the court. The person seeking the service or his attorney may designate any qualified newspaper, and if he fails to do so, the selection may be made by the clerk. Service of summons by publication shall be made and procured by the clerk, by a person appointed by the court for that purpose, or by the clerk or sheriff of another county where publication is to be made.
The return and affidavits shall be filed with the pleadings and other papers in the case and shall become a part of the record as provided in these rules. Service Under Special Order of Court Upon application of any party the court in which any action is pending may make an appropriate order for service in a manner not provided by these rules or statutes when such service is reasonably calculated to give the defendant actual knowledge of the proceedings and an opportunity to be heard.
The latter only applies to array names: variables declared with subscripts int A. However, arrays created by dynamic allocation are accessed by pointers rather than true array variables, so they suffer from the same sizeof issues as array pointers. Thus, despite this apparent equivalence between array and pointer variables, there is still a distinction to be made between them.
Even though the name of an array is, in most expression contexts, converted into a pointer to its first element , this pointer does not itself occupy any storage; the array name is not an l-value , and its address is a constant, unlike a pointer variable. Consequently, what an array "points to" cannot be changed, and it is impossible to assign a new address to an array name. Array contents may be copied, however, by using the memcpy function, or by accessing the individual elements.
Memory management[ edit ] One of the most important functions of a programming language is to provide facilities for managing memory and the objects that are stored in memory. C provides three distinct ways to allocate memory for objects:  Static memory allocation : space for the object is provided in the binary at compile-time; these objects have an extent or lifetime as long as the binary which contains them is loaded into memory. Automatic memory allocation : temporary objects can be stored on the stack , and this space is automatically freed and reusable after the block in which they are declared is exited.
Dynamic memory allocation : blocks of memory of arbitrary size can be requested at run-time using library functions such as malloc from a region of memory called the heap ; these blocks persist until subsequently freed for reuse by calling the library function realloc or free These three approaches are appropriate in different situations and have various trade-offs.
For example, static memory allocation has little allocation overhead, automatic allocation may involve slightly more overhead, and dynamic memory allocation can potentially have a great deal of overhead for both allocation and deallocation.
The persistent nature of static objects is useful for maintaining state information across function calls, automatic allocation is easy to use but stack space is typically much more limited and transient than either static memory or heap space, and dynamic memory allocation allows convenient allocation of objects whose size is known only at run-time.
Most C programs make extensive use of all three. Where possible, automatic or static allocation is usually simplest because the storage is managed by the compiler, freeing the programmer of the potentially error-prone chore of manually allocating and releasing storage. However, many data structures can change in size at runtime, and since static allocations and automatic allocations before C99 must have a fixed size at compile-time, there are many situations in which dynamic allocation is necessary.
See the article on malloc for an example of dynamically allocated arrays.
Unlike automatic allocation, which can fail at run time with uncontrolled consequences, the dynamic allocation functions return an indication in the form of a null pointer value when the required storage cannot be allocated. Static allocation that is too large is usually detected by the linker or loader , before the program can even begin execution. Unless otherwise specified, static objects contain zero or null pointer values upon program startup.
Automatically and dynamically allocated objects are initialized only if an initial value is explicitly specified; otherwise they initially have indeterminate values typically, whatever bit pattern happens to be present in the storage , which might not even represent a valid value for that type. If the program attempts to access an uninitialized value, the results are undefined. Many modern compilers try to detect and warn about this problem, but both false positives and false negatives can occur.
Another issue is that heap memory allocation has to be synchronized with its actual usage in any program in order for it to be reused as much as possible. For example, if the only pointer to a heap memory allocation goes out of scope or has its value overwritten before free is called, then that memory cannot be recovered for later reuse and is essentially lost to the program, a phenomenon known as a memory leak.
We previously reported discovery of a panel of mouse monoclonal antibodies mAbs against rat DPP-IV that could complement known competitive small molecule inhibitors These inhibitory antibodies to rat DPP-IV showed notable in vivo efficacy in hyperglycemic Zucker fatty rats in terms of improving glucose tolerance. Interestingly, the structural data also revealed a possibility for small molecules to access the active site in the presence of the blocking antibody, 11A Indeed, we were able to generate a co-crystal structure of the ternary complex of rat DPP-IV with both 11A19 Fab and a small molecule inhibitor sitagliptin PDB code: 4FFW , demonstrating the simultaneous binding of the two molecules, with the Fab on the surface and the small molecule inhibitor in the deep catalytic pocket Together, the two structures rationalize the partial inhibitory activity profile of the antibodies towards peptide substrates due to the fact that the antibody was not fully blocking the active site.
Moreover, the ternary structure revealed an attractive opportunity to link 11A19 Fab and sitagliptin together, and inspired us to apply a rational design and synthetic chemistry approach to engineering a hybrid.
We hypothesized that such a hybrid could be more potent than either the antibody or small molecule alone due to the chelate effect 12 , and that the small molecule would confer improved inhibition of DPP-IV as well as improved selectivity.
Results To generate a small molecule-antibody hybrid, we needed first to engineer antibody variants and small molecule analogs as precursors for conjugation reactions. On the antibody side, we looked to engineer a cysteine residue that would provide a reactive thiol handle for conjugation of a PEG linker.
Using our ternary structure of DPP-IV complexed with 11A19 Fab and sitagliptin PDB code: 4FFW , we looked for antibody residue positions that met four criteria: high solvent exposure, minimal involvement in DPP-IV recognition, short distance to the bound small molecule inhibitor, and side-chain oriented in the direction of the substrate pocket.
All three Cys variants of 11A19 were generated successfully. Compared with the wild type Fab, with a Kd of 1. Three residues on the Fab identified as potential conjugation sites are labeled and shown in stick.
Full size image On the small molecule side, known structure-activity-relationships 13 , 14 of DPP-IV inhibitors together with the inhibitor co-crystal structure informed design of small molecule analogs likely to largely retain potency while enabling conjugation chemistry.
We started from sitagliptin, compound 1 Fig. We then prepared the acid analog, 3, to serve as an intermediate for conjugation. We did not further optimize 2, but published data suggests that further optimization, particularly around the piperazine ring 14 , should improve potency.
Figure 2 Designed small molecule SM analog structures. For 4—9, n indicates number of PEG units. Left panel: number of low energy conformations in the modeled bound conformation. Right panel: calculated strain energy in lowest energy conformation found, where lower strain energies are expected to be favorable. See Methods for additional details.
To identify an optimal linker, we modeled the bound state of several linker compositions and gauged their flexibility and strain computationally by performing extensive conformational searches see Methods for details.
A linker which is too short to deliver a potency boost would have high strain. On the other hand, a linker that is too long would have a high number of thermodynamically-accessible linker conformations and would begin to lose the synergistic effects on potency In addition, different linker lengths have different conformational preferences.
We modeled a number of peptide-based linkers and initially tested poly-Ala, but PEG had much improved solubility. Molecular modeling of the molecules followed by estimation of linker conformations and linker strain, as shown in Fig. To assemble the complete hybrid molecules, the engineered cysteine residues Cys30 in the Fab and IgG variants were reduced with tris- 2-carboxyethyl phosphine TCEP.
A series of analogs, 6, with a PEG linker and no Fab or antibody attached, were synthesized as negative controls Fig. A series of chemibodies, 7—9, were generated by conjugating analog 5 with 11A19 IgG and 11A19 Fab harboring N30C mutations, as well as to a negative control Fc molecule Fig.
Additional details for the conjugation chemistry are described in the online Methods. IC50 results for these molecules are shown in Fig.
Analogs 6, with PEG linker but no Fab or antibody tethered, had similar potency to analog 2 irrespective of the number of PEG units in the linker. Analogs 8 with Fab attached showed strikingly distinct activity differences between molecules with 3—4 PEG units and molecules with 5—8 PEG units. Figure 3 Biochemical assay results. All measurements were done in triplicate and error bars are provided for b—e. Note only some error bars are noticeable due to very tight assay results.
Full size image In addition, this initial hybrid molecule has substantial room for further improvement.